EP1556347A2 - Gamma lactames utilises en tant qu'agonistes de la prostaglandine et leur utilisation - Google Patents

Gamma lactames utilises en tant qu'agonistes de la prostaglandine et leur utilisation

Info

Publication number
EP1556347A2
EP1556347A2 EP03736967A EP03736967A EP1556347A2 EP 1556347 A2 EP1556347 A2 EP 1556347A2 EP 03736967 A EP03736967 A EP 03736967A EP 03736967 A EP03736967 A EP 03736967A EP 1556347 A2 EP1556347 A2 EP 1556347A2
Authority
EP
European Patent Office
Prior art keywords
enyl
oxopyrrolidin
ethyl
benzoic acid
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03736967A
Other languages
German (de)
English (en)
Other versions
EP1556347A4 (fr
Inventor
Gian Luca Araldi
Adulla P. Reddy
Zhong Zhao
Sean D. Mckenna
Bagna Bao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Serono SA
Original Assignee
Applied Research Systems ARS Holding NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Applied Research Systems ARS Holding NV filed Critical Applied Research Systems ARS Holding NV
Publication of EP1556347A2 publication Critical patent/EP1556347A2/fr
Publication of EP1556347A4 publication Critical patent/EP1556347A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention provides substituted 1,2-substituted 5-pyrrolidinone compounds, methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds.
  • Compounds of the invention are useful for a variety of therapies, including preterm labor, ovulation induction, cervical ripening, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, including erectile dysfunction, osteoporosis and other destructive bone disease or disorder, renal dysfunction (acute and chronic), immune deficiency disorder or disease, dry eye, skin disorders such as ichthyosis, elevated intra-ocular pressure such as associated with glaucoma, sleep disorders, ulcers, inflammatory disorders and other diseases and disorders associated with the prostaglandin and receptors thereof.
  • the invention further provides methods and pharmaceutical compositions comprising prostaglandin EP4 receptor agonists for the treatment of infertility
  • Prostaglandins which belong to the prostanoids family are known to have diverse biological activities such as contraction and relaxation of smooth muscle, inhibition and enhancement of neuro transmitter release, inhibition of lipolysis, inhibition of gastric secretion, inhibition of inflammatory mediator release (Coleman et al.
  • EP4 See also U.S. Patents 5,605,814 and 5,759,789. Knock-out mice lacking each type and sub-type of the EP receptor showed different roles for these receptors (Ushikubi at al. 2000, Jpn. J. Pharmacol. 83, 279-285) in various mechanisms such as ovulation, blood pressure control, closure of ductus arteriosus and bone resorption. Additional roles of EP receptors have been reported such as smooth muscle relaxation in cat trachea for EP2, vasodilatation for EP4 (Gardinier, Br. J. Pharmac. 1986, 87, 45-56; Coleman et al. 1994 Pharmacological Reviews 46 (2), 205-229) and anti-inflammatory activity for EP4 (Takayama et al.
  • Renal Prostaglandin E2 (PGE2) is crucial of normal renal function by dilating the glomerular microcirculation and vasa recta, supplying the renal medulla and modulating salt and water transport in the distal tubule.
  • Prostaglandin E2 (PGE2) is a natural ligand for all sub-types of the EP receptor. Consequently, selective effects on one of the sub-types of the EP receptor is impossible to achieve with the endogenous prostaglandins.
  • prostaglandin ligands and analogs have been reported to provide biological activity associated with prostaglandins (U.S. 6,288,120; US 6,211,197; US 4,090,019; US 4,033,989; US 4,003,911).
  • ⁇ -type prostaglandin reported to be mediated through interaction with the prostaglandin ⁇ receptor(s).
  • Certain compounds also have been reported as ⁇ P4 agonists (WO 02/24647, EP 1110949A1, WO03/009872 and WO 03/007941).
  • substituted 1,2-substituted 5-pyrrolidinone compounds that are useful for a variety of therapies, including alleviating, preventing and/or treating preterm labor, ovulation induction, cervical ripening, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, including erectile dysfunction, osteoporosis and other destructive bone disease or disorder, renal dysfunction (acute and chronic), immune deficiency disorder or disease, dry eye, skin disorders such as ichthyosis, elevated intra-ocular pressure such as associated with glaucoma, sleep disorders, ulcers, inflammatory disorders and other diseases and disorders associated with the prostaglandin family of compounds and receptors thereof.
  • the invention particularly provides methods of inducing ovulation, particularly ovulation triggering, in a mammal comprising administering an EP4 receptor agonist, an isomer thereof, a pro-drug of said agonist or isomer, or a pharmaceutically acceptable salt of said agonist, isomer or pro-drug.
  • A is hydrogen or hydroxy
  • B is selected from the group comprising or consisting of optionally substituted carbocyclic aryl, optionally substituted heteroalicyclic having from 3 to 8 ring atoms and at least one N, O or S ring atom and a heteroaromatic group having a single ring with 5 or 6 ring atoms and at least one N, O or S ring atom;
  • U is (CH 2 ) p wherein p is selected from 0, 1 and 2;
  • V and Q are each independently selected from the group comprising or consisting of hydrogen, optionally substituted alkyl preferably having 1 to about 12 carbon atoms, optionally substituted alkenyl preferably having 2 to about 12 carbon atoms, optionally substituted alkynyl preferably having from 2 to about 12 carbon atoms, optionally substituted C ⁇ -C 6 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl Ci-C ⁇ alkyl, optionally substituted C -C 6 heterocycloalkyl Ci-C 6 alkyl, optionally substituted aryl C ⁇ -C 6 alkyl and -CR 1 R 2 -W, wherein R 1 and R 2 are independently selected from H and optionally substituted Ci-C 6 alkyl, preferably H; or R 1 and R 2 can form an optionally substituted C 3 -C 6 cycloalkyl with the carbon they are attached to, preferably an optionally substituted C 3 , C 4 or C 5 cycloalkyl;
  • W is selected from the group comprising or consisting of hydrogen, optionally substituted C ⁇ -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted
  • substituent B is a substituted carbocyclic aryl, heteroalicyclic, or heteroaromatic group, e.g. such a ring group substituted by a carboxylate (e.g. -COOR where R is hydrogen or C ⁇ -C 6 alkyl), amide (e.g. -CONFER where R is H is C ⁇ -C 6 alkyl), and the like.
  • Preferred compounds of Formula I include those compounds where substituent A is hydrogen and/or substituent B is an optionally substituted thiophene, optionally substituted furan or optionally substituted carbocyclic aryl group particularly optionally substituted phenyl, such as compounds ofthe following Formula II:
  • X is selected from oxygen, sulfur, sulfmyl (SO), sulfonyl (SO 2 ) and carbon, preferably is methylene (-CH 2 -);
  • C ⁇ -C ester including methyl, ethyl, propyl or butyl esters
  • optionally substituted alkyl preferably C ⁇ C 6 alkyl or R is amino or alkylamine such as — NR J R 2 where R 1 and R are independently hydrogen or optionally substituted alkyl preferably -Cg alkyl having 1 to 6; n is an integer selected from 0, 1, 2, 3, 4 (where available phenyl ring positions are all hydrogen-substituted) and 5, and preferably n is selected from 0, 1 and 2; and pharmaceutically acceptable salts thereof.
  • Preferred compounds of Formulae I and II above include those having a para- substituted phenyl moiety as a component of the substituent of the pyrrolidinone ring nitrogen, such as compounds of following Formula III:
  • Q and N is hydrogen and the other is a non-hydrogen group, such as compounds of the following Formula IN:
  • R and n are the same as defined in Formula II;
  • Q is selected from the group comprising or consisting of optionally substituted alkyl preferably having 1 to about 12 carbon atoms, optionally substituted alkenyl preferably having 2 to about 12 carbon atoms, optionally substituted alkynyl preferably having from 2 to about 12 carbon atoms, C ⁇ -C 6 heteroalkyl, C 3 -C 6 cycloalkyl C ⁇ -C 6 alkyl, C 3 -C 6 heterocycloalkyl C ⁇ -C 6 alkyl, optionally substituted arylalkyl and -CR R -
  • R 1 and R 2 are independently selected from H and optionally substituted Ci-
  • R 1 and R 2 can form an optionally substituted C 3 -C 6 cycloalkyl with the carbon they are attached to, preferably an optionally substituted C 3 ,
  • W is selected from the group comprising or consisting of hydrogen, optionally substituted C ⁇ -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted
  • R and n are the same as defined in Formula II;
  • Q is selected from the group comprising or consisting of optionally substituted (straight or branched) alkyl preferably having 1 to about 12 carbon atoms, more preferably from 1 to 9 carbon atoms (e.g. a pentyl, hexyl, heptyl or nonyl moiety), optionally substituted alkenyl preferably having 2 to about 12 carbon atoms, optionally substituted alkynyl preferably having from 2 to about 12 carbon atoms, C ⁇ -C 6 heteroalkyl, C 3 -C 6 cycloalkyl C ⁇ -C 6 alkyl, C 3 -C 6 heterocycloalkyl C ⁇ -C 6 alkyl, optionally substituted arylalkyl, e.g.
  • R 1 and R 2 are independently selected from H and optionally substituted C ⁇ -C 6 alkyl, preferably H or methyl; or R 1 and R 2 can form an optionally substituted C -C 6 cycloalkyl with the carbon they are attached to, preferably an optionally substituted C or C 4 cycloalkyl;
  • W is selected from the group comprising or consisting of hydrogen, optionally substituted C ⁇ -C 6 alkyl, optionally substituted C -C 6 cycloalkyl, optionally substituted
  • R 1 and R 2 are independently selected from H and optionally substituted C ⁇ -C 6 alkyl, preferably H or methyl; or R 1 and R 2 can form an optionally substituted C 3 -C 6 cycloalkyl with the carbon they are attached to, preferably an optionally substituted C 3 or C 4 cycloalkyl;
  • W is selected from the group comprising or consisting of hydrogen, optionally substituted C ⁇ -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 cycloalkyl C ⁇ -C 6 alkyl, optionally substituted aryl and optionally substituted aryl C ⁇ -C 6 alkyl; and pharmaceutically acceptable salts thereof.
  • R 1 optionally substituted C ⁇ -C 6 alkyl, preferably H or methyl; or R and R can form an optionally substituted C 3 -C 6 cycloalkyl with the carbon they are attached to, preferably an optionally substituted C or C cycloalkyl;
  • W is selected from the group comprising or consisting of hydrogen, optionally substituted C ⁇ -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl C ⁇ -C 6 alkyl and optionally substituted aryl; and pharmaceutically acceptable salts thereof.
  • the compounds of the invention exhibit binding activity in a standard prostaglandin EP2 receptor binding assay. Exemplary assay is set out in Example 81, which follows. According to one embodiment, compounds of the present invention also can exhibit selective binding to the EP4 receptor.
  • substituted 1,2-substituted 5-pyrrolidinone compounds of the invention are useful for treatment of diseases and disorders associated with the prostaglandin family of compounds.
  • Therapeutic methods of the invention in general comprise administering an effective amount of one or more 1,2-substituted 5- pyrrolidinone compounds as disclosed herein to a mammal in need thereof.
  • 1,2-substituted 5-pyrrolidinone compounds of the invention are particularly useful for treatment of a mammal suffering from or susceptible to (prophylactic therapy) pre-term labor, dysmenorrhea, asthma and other conditions treated by bronchodilation, inflammation, hypertension, undesired blood-clotting and other undesired platelet activities, pre-eclampsia and/or eclampsia, and eosinphil-related disorders.
  • 1,2- substituted 5-pyrrolidinone compounds of the invention also are useful to treat a mammal suffering from or suspected of suffering from infertility, particularly a female suffering from infertility.
  • 1,2-substituted 5-pyrrolidinone compounds of the invention may be particularly beneficial for treatment of female mammals suffering from an ovulatory disorder. Additionally, 1,2-substituted 5-pyrrolidinone compounds of the invention can be administered to females undergoing reproductive treatments such as in- vitro fertilization or implant procedures, e.g. to stimulate follicular development and maturation. 1,2-substituted 5-pyrrolidinone compounds of the invention also are useful to treat sexual dysfunction, including erectile dysfunction.
  • Preferred 1,2-substituted 5-pyrrolidinone compounds of the invention also will be useful for treatment of undesired bone loss (e.g. osteoporosis, particularly in women) or otherwise promoting bone formation and treatment of other bone diseases such as Paget's disease, healing or replacement of bone grafts, and the like.
  • undesired bone loss e.g. osteoporosis, particularly in women
  • other bone diseases such as Paget's disease, healing or replacement of bone grafts, and the like.
  • Compounds of the invention also are useful for treatment of a subject suffering from or susceptible to renal dysfunction, including a mammal suffering from or susceptible to acute or chronic renal failure.
  • Compounds of the invention also are useful for treatment of a subject suffering from or susceptible to an immune disorder including an immune deficiency disease or disorder, including such a disorder associated with a viral infection particularly a retroviral infection such as an HIN infection.
  • Particularly benefited by such therapies will be a human suffering from or susceptible to ALUS (Thivierge et al. Blood, 1998, 92 (1), 40-45).
  • Compounds ofthe invention will be further useful to reduce elevated intra-ocular pressure of a subject, e.g. through relaxation of pre-contracted isolated ciliary muscle.
  • a mammal such as a human suffering from or susceptible to glaucoma or other disorder associated with elevated intra-ocular pressure.
  • Compounds of the invention also will be useful for treatment of a mammal, particularly a human, that is suffering from or susceptible to dry eye.
  • Compounds of the invention also will be useful for promoting sleep in a subject, e.g. to treat a mammal particularly a human suffering from or susceptible to a sleep disorder such as may be associated with advanced age, such as a human of 65 years or older.
  • Compounds ofthe invention also will be useful to treat a mammal suffering from or susceptible to a sexual dysfunction, particularly a human male suffering from erectile dysfunction.
  • Compounds of the invention also will be useful to treat a amman suddering from or susceptible to an inflammatory disease or disorder including vascular inflammation, inflammatory pain and hyperalgesia.
  • Compounds of the invention will be further useful to treat a mammal suffering from or susceptible to ulcers, particularly gastric ulcers.
  • Such therapies may be conducted in conjunction with a patient being treated with an anti-inflammatory agent, which can promote gastric ulcers-
  • Compounds ofthe invention also may be administered to a mammal particularly a human that is suffering from or susceptible to a skin disorder, particularly dry skin (ichthyosis) or skin rash.
  • the invention provides a use of a 1,2-substituted 5- pyrrolidinone compound, including a particularly of any one of Formulae I through N for the treatment or prevention (including prophylactic treatment) of a disease or condition as disclosed herein, including pre-term labor, ovulation induction, cervical ripening, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, undesired blood clotting, pre-eclampsia or eclampsia, an eosinophil disorder, sexual dysfunction including erectile dysfunction, osteporosis and other destructive bone disease or disorder, renal dysfunction (acute and chronic), immune deficiency disorder or disease, dry eye, skin disorders such as ichthyosis, elevated intra-ocular pressure such as associated with glaucoma, sleep disorders, ulcers, inflammatory diseases or disorders and other diseases and disorders associated with the prostaglandin and receptors thereof .
  • the invention provides a use of a 1,2-substituted 5- pyrrolidinone compound, particularly a compound of any one of Formulae I through N for the preparation of a medicament for the treatment or prevention (including prophylactic treatment) of a disease or condition as disclosed herein, including pre-term labor, ovulation induction, cervical ripening, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, undesired blood clotting, pre-eclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, including erectile dysfunction, osteoporosis and other destructive bone disease or disorder, renal dysfunction (acute and chronic), immune deficiency disorder or disease, dry eye, skin disorders such as ichthyosis, elevated intra-ocular pressure such as associated with glaucoma, sleep disorders, ulcers, inflammatory diseases or disorders and other diseases and disorders associated with the prostaglandin and receptors thereof
  • Preferred methods of the invention including identifying and/or selecting a subject (e.g. mammal, particularly human) that is susceptible to or suffering from a condition disclosed herein, and thereafter administering to the identified and selected subject one or more compounds of the invention, particularly a subject that is identified and selected as being susceptible to or suffering from infertility, particularly anovulatory disorders, pre-term labor, asthma, hypertension, sexual dysfunction,including erectile dysfunction, osteoporosis and other destructive bone disease or disorder, inflammation, renal dysfunction (acute and chronic), immune deficiency disorder or disease, dry eye, skin disorders such as ichthyosis, elevated intra-ocular pressure such as associated with glaucoma, sleep disorders, ulcers, or other diseases and disorders associated with prostaglandin.
  • a subject e.g. mammal, particularly human
  • infertility particularly anovulatory disorders, pre-term labor, asthma, hypertension, sexual dysfunction,including erectile dysfunction, osteoporosis and other destructive bone disease or disorder, inflammation, renal
  • the invention also provides pharmaceutical compositions that comprise one or more 1,2-substituted 5-pyrrolidinone compounds together with a suitable carrier for the com ⁇ ound(s).
  • the invention provides methods and pharmaceutical compositions comprising administering a prostaglandin EP4 receptor agonist for the treatment of infertility, including ovulatory disorders. More specifically, the present invention relates to such methods and pharmaceutical compositions for inducing ovulation, including ovulation triggering: more specifically, for triggering ovulation in a patient under a treatment for ovulation induction or under ART (Assisted Reproductive Technology) therapies.
  • ART Assisted Reproductive Technology
  • the invention provides methods and pharmaceutical compositions comprising administering a prostaglandin EP4 receptor agonist for the treatment of infertility disorders wherein the EP4 agonist is selected among compounds of following formula NI:
  • A is H or OH, preferably H
  • B is selected from the group comprising or consisting of optionally substituted C ⁇ -C 6 alkyl, preferably C 3 or C 4 alkyl, optionally substituted aryl C ⁇ -C 6 alkyl, optionally substituted aryl C ⁇ -C 6 heteroalkyl, preferably aryl C ⁇ -C 6 alkoxy, optionally substituted heteroaryl C ⁇ -C 6 alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 6 cycloalkyl and optionally substituted C 3 -C 6 heterocycloalkyl, provided that when B is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 6 cycloalkyl and optionally substituted C 3 -C 6 heterocycloalkyl, the undefined bond linking B is a single bond;
  • the dotted line indicates an optional double bond;
  • Ci_C ester including methyl, ethyl, propyl or butyl esters), optionally substituted alkyl, preferably C ⁇ -C 6 alkyl and optionally substituted aryl; or Z is selected from the group comprising or consisting of amino or alkylamine such as -I ⁇ D ⁇ R 2 wherein R 1 and R 2 are independently selected from hydrogen and optionally substituted alkyl, preferably C ⁇ _C 6 alkyl, - ⁇ HSO 2 R 3 and -NHC(O)R 3 wherein R 3 is selected among optionally substituted C ⁇ -C 6 alkyl and optionally substituted aryl; or R is optionally substituted heteroaryl, preferably including at least one N atom, including tetrazolyl;
  • U is (CH ) P wherein p is an integer selected from 0, 1 and 2, preferably 0 or 1;
  • Q is -CR 4 R 5 -W, wherein R 4 and R 5 are independently selected from H, halogen and optionally substituted C ⁇ -C 6 alkyl; or R 4 and R 5 can form an optionally substituted C -C 6 cycloalkyl with the carbon they are attached to, preferably an optionally substituted C 3 , C 4 or C 5 cycloalkyl;
  • W is selected from the group comprising or consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C -C 6 cycloalkyl, optionally substituted C 3 -C 6 heterocycloalkyl, optionally substituted C 3 -C 6 cycloalkyl C ⁇ -C 6 alkyl, optionally substituted C 3 -C 6 heterocycloalkyl C ⁇ -C 6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl C ⁇ C 6 alkyl and optionally substituted heteroaryl C ⁇ -C 6 alkyl; and pharmaceutically acceptable salts thereof.
  • Preferred said EP4 agonists are selected in an EP4 binding assay.
  • An example of such an assay is defined in Example 83 which follows.
  • Figure 1 reports the number of ova released after s.c. injection of compound of Example 1 in mature 10- week CD-I mice, 48 hours after an injection of 5IU PMSG
  • Figure 2 reports the number of ova released after oral administration of compound of Example 1 in mature 10- week CD-I mice, 48 hours after an injection of 5IU PMSG (i.p.). The number of ova released is shown for different doses of oral administration of compound of Example 1.
  • Figure 3 reports the number of ova released after oral administration of compounds ofthe invention at the single dose of 20 mg/kg.
  • 1,2-substituted 5-pyrrolidinone compounds of the above Formulae I, II, III, IN and N are useful for treatment of a variety of disorders, particularly diseases and disorders associated with prostaglandins, such as by inhibiting prostanoid-induced smooth muscle contraction.
  • Suitable alkyl substituent groups of compounds of the invention typically have from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1, 2, 3, 4, 5, or 6 carbon atoms.
  • alkyl refers to both cyclic and noncyclic as well as branched and straight groups, although of course cyclic groups will comprise at least three carbon ring members.
  • Preferred alkenyl and alkynyl groups of compounds of the invention have one or more unsaturated linkages and typically from 2 to about 12 carbon atoms, more preferably 2 to about 8 carbon atoms, still more preferably 2, 3, 4, 5, or 6 carbon atoms.
  • alkenyl and alkynyl as used herein refer to both cyclic and noncyclic groups, although straight or branched noncyclic groups are generally more preferred.
  • Preferred alkoxy groups of compounds of the invention include groups having one or more oxygen linkages and from 1 to about 8 carbon atoms, and still more preferably 1, 2, 3, 4, 5 or 6 carbon atoms.
  • Preferred alkyiamino groups include those groups having one or more primary, secondary and/or tertiary amine groups, and from 1 to about 8 carbon atoms, still more preferably 1, 2, 3, 4, 5, or 6 carbon atoms.
  • Suitable heteroalicyclic groups of compounds of the invention particularly as substituent B as Formula I contain one or more N, O or S atoms and include, e.g., tetrahydrofuranyl, thienyl, piperidinyl, morpholino and pyrrolidinyl groups.
  • Suitable heteroaromatic groups of compounds of the invention particularly as substituent B as Formula I are 5-membered or 6-membered single ring moieties having at least N, O or S rings atoms.
  • Particular examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, furyl (furanyl), thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3- oxadiazolyl, 1,2,4-oxadia-zolyl, 1,2,5-oxadiazolyl, l,3,4-oxadiazolyl,l,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazo
  • Suitable carbocyclic aryl groups of compounds of the invention include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups.
  • Typical carbocyclic aryl groups of compounds of the invention contain 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms.
  • Specifically preferred carbocyclic aryl groups include phenyl; naphthyl including phenyl, 1 -naphthyl and 2-naphthyl; biphenyl; phenanthryl; anthracyl; and acenaphthyl.
  • Substituted carbocyclic groups are particularly suitable including substituted phenyl, such as 2-substituted phenyl, 3-substituted phenyl, 4-substiruted phenyl, 2,3-substituted phenyl, 2,4-substituted phenyl, and 2,5-substituted phenyl; and substituted naphthyl, including naphthyl substituted at the 5, 6 and/or 7 positions.
  • substituted phenyl such as 2-substituted phenyl, 3-substituted phenyl, 4-substiruted phenyl, 2,3-substituted phenyl, 2,4-substituted phenyl, and 2,5-substituted phenyl
  • substituted naphthyl including naphthyl substituted at the 5, 6 and/or 7 positions.
  • Suitable aralkyl groups of compounds of the invention include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused carbocyclic aryl groups.
  • Typical aralkyl groups contain 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms.
  • Preferred aralkyl groups include benzyl and naphthylmethyl (-CH 2 -naphthyl), and other carbocyclic aralkyl groups, as discussed above.
  • R, R 1 , R 2 , B, N, Q, and Z may be optionally substituted.
  • a "substituted" R, R 1 , R 2 , B, N, Q, and Z group or other substituent may be substituted by other than hydrogen at one or more available positions, typically 1 to 3 or 4 positions, by one or more suitable groups such as those disclosed herein.
  • suitable groups that may be present on a "substituted" R, R 1 , R 2 , B, V, Q, and Z group or other substituent include e.g.
  • halogen such as fluoro, chloro, bromo and iodo; cyano; hydroxyl; nitro; azido; alkanoyl such as a C ⁇ _ 6 alkanoyl group such as acyl and the like; carboxamido; alkyl groups including those groups having 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon, or 2, 3, 4, 5 or 6 carbon atoms; alkoxy groups including those having one or more oxygen linkages and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5 or 6 carbon atoms; aryloxy such as phenoxy; alkyiamino groups such as groups having one or more ⁇ atoms and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5 or 6 carbon atoms; carbocyclic aryl having 6 or more carbons; aralkyl having 1
  • Also comprised by the term optionally substituted shall be situations where at one position of a moiety R, R 1 , R 2 , B, N, Q, Z two alkyl substituents undergo ring closure to provide for a cycloalkyl, e.g. a cyclopropyl, moiety.
  • a particularly preferred embodiment ofthe invention is the group of pyrrolidine derivatives according to formula N wherein R is -C(O)OH being in a "para" position whereby n is 1.
  • Another particularly preferred embodiment of the invention includes compounds of formula N, wherein R is -C(O)OH being in a "para" position whereby n is 1;
  • Q is selected from the group comprising or consisting of optionally substituted C ⁇ -C 6 alkyl, preferably butyl, pentyl, hexyl, methyl butyl, methyl propyl, di-methyl propyl, di-methyl pentyl or trifluoropropyl, optionally substituted C -C 6 alkenyl, preferably butenyl, optionally substituted C -C 6 alkynyl and -CR 1 R 2 -W, wherein R 1 and R 2 are independently selected from H and optionally substituted C ⁇ -C 6 alkyl, preferably H or methyl; or R 1 and R 2 can form an optionally substituted C 3 -C 6 cycloalkyl with the carbon they are attached to, preferably an optionally substituted C 3 or C 4 cycloalkyl, preferably cyclopropyl or cyclobutyl;
  • W is selected from the group comprising or consisting of hydrogen, optionally substituted C ⁇ -C 6 alkyl, preferably propyl, butyl, pentyl, methyl- 1 -ethyl, methyl propyl, tert-butyl or tri-fluoro ethyl, optionally substituted C 3 -C 6 cycloaUcyl C ⁇ -C 6 alkyl, preferably, methyl cyclopropyl, ethyl cyclopropyl, optionally substituted C 3 -C 6 cycloalkyl, preferably cyclopropyl, cyclopentyl or cyclohexyl, optionally substituted aryl, preferably optionally substituted phenyl including phenyl, methyl phenyl, halogeno phenyl and chloro phenyl and optionally substituted aryl C ⁇ -C 6 alkyl, preferably ethyl phenyl; and pharmaceutically acceptable salts thereof.
  • Another more preferred group of compounds of the invention includes compounds of formula N wherein R is -C(O)OH being in a "para" position whereby n is 1; Q is -CR ⁇ -W, wherein R 1 and R 2 are independently selected from H and optionally substituted C ⁇ -C 6 alkyl, preferably H or methyl; or R 1 and R 2 can form an optionally substituted C 3 -C 6 cycloalkyl with the carbon they are attached to, preferably an optionally substituted C or C 4 cycloalkyl, preferably cyclopropyl or cyclobutyl;
  • W is selected from the group comprising or consisting of hydrogen, optionally substituted C ⁇ -C 6 alkyl, preferably propyl, butyl, pentyl, optionally substituted C 3 -C 6 cycloalkyl C ⁇ -C 6 alkyl, preferably methyl cyclopropyl or ethyl cyclopropyl and optionally substituted aryl, preferably optionally substituted phenyl including phenyl and methyl phenyl; and pharmaceutically acceptable salts thereof.
  • pyrrolidinones of the invention include the following depicted compounds and pharmaceutically acceptable salts of these compounds:
  • preferred compounds of the invention exhibit activity in a prostaglandin EP2 receptor binding assay as described, for example in the protocol of
  • Example 81 which follows.
  • Generally preferred compounds of the invention have a Ei
  • ⁇ M of about 100 or less, more preferably about 50 or less, still more preferably a Ki ( ⁇ M) of about 10 or 20 or less, even more preferably a Ki ( ⁇ M) of about 5 or less in such a prostaglandin assay as exemplified by Example 81 which follows.
  • 1,2-substituted 5-pyrrolidinone compounds of the invention can be readily prepared. Suitable synthetic procedures are exemplified in the following Scheme 1. It should be appreciated that the compounds shown in the following Scheme is exemplary only, and a variety of other compounds can be employed in a similar manner as described below.
  • kits and pharmaceutical compositions comprising administering a prostaglandin EP4 receptor agonist for the treatment of infertility, including ovulatory disorders. More specifically, the present invention relates to such methods and pharmaceutical compositions for inducing ovulation, particularly ovulation triggering; more specifically, the present invention relates to such methods and pharmaceutical compositions for triggering ovulation in patients under ovulation induction or ART treatments.
  • EP4 receptor agonist refers to a compound, including its isomers, pro-drugs and pharmaceutically acceptable salts, which bind to the prostaglandin EP4 sub-type receptor.
  • a prostaglandin EP4 sub-type agonist can be identified by several conventional assays, including a prostaglandin EP4 binding assay and a cyclic AMP assay on cells over-expressing EP4 receptor. Other appropriate conventional assays may be used by the skilled person in the art for selecting EP4 agonists.
  • Preferred prostaglandin EP4 receptor agonists exhibit activity in a prostaglandin EP4 receptor binding assay, an example thereof is defined in the protocol as defined in Example 83, which follows.
  • a particularly preferred group of EP4 receptor agonists of the invention have a
  • Other preferred prostaglandin EP4 receptor agonists exhibit activity in a cAMP assay on cell lines over-expressing EP4 receptor, an example thereof is defined in the protocol as defined in Example 84, which follows.
  • EP4 receptor agonists of the invention have a EC 50 (nM) of about 30 or less, more preferably about 20 or less, still more preferably a EC 50 (nM) of about 10 or 5 or less, even more preferably a EC 5 rj (nM) of about 1 or 0.1 less in such a cAMP/EP4 receptor as exemplified by Example 84 which follows.
  • the selective EP4 receptor agonists used for triggering ovulation can be selected from EP4 agonists described in the art that have the preferred EP4 activities mentioned above in EP4 assays.
  • EP4 selective agonists can be selected from EP4 agonists described in WO 03/035064, preferably 4- [2-(2- ⁇ 3 -hydroxy-4- [3 -(trifluoromethyl)phenyl]butyl ⁇ -5 -oxopyrazolidin- 1 - yl)ethyl]benzoic acid and 4-(2- ⁇ 2-[4-(3-iodophenyl)-3-hydroxybutyl]-5-oxopyrazolidin- l-yl ⁇ ethyl)benzoic acid.
  • the said method for inducing ovulation is a method wherein said EP4 agonist is selected among compounds of Formula NI, wherein the substituents A, B, D, R, U, Q, W, R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined in Formula NI above.
  • C ⁇ -C 4 ester including methyl, ethyl, propyl or butyl esters
  • optionally substituted alkyl preferably C ⁇ -C 6 alkyl
  • Z is selected from amino or alkylamine such as -NR ⁇ 2 where R 1 and R 2 are independently hydrogen or optionally substituted alkyl, preferably C ⁇ _C 6 alkyl, -NHSO 2 R 3 and -NHC(O)R 3 wherein R 3 is selected among optionally substituted C ⁇ _C 6 alkyl and optionally substituted aryl
  • U is (CH 2 ) P wherein p is 0;
  • Q is -CR 4 R 5 -W, wherein R 4 and R 5 are independently selected from H, halogen and optionally substituted C ⁇ -C 6 alkyl;
  • W is selected from optionally substituted C -C 6 cycloalkyl, optionally substituted C 3 -C 6 heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R is optionally substituted heteroaryl, preferably including at least one N atom, including tetrazolyl;
  • U is (CH ) P wherein p is 0;
  • Q is -CH 2 -W, wherein W is selected from optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; and pharmaceutically acceptable salts thereof.
  • N atom including tetrazolyl
  • U is (CH 2 ) P wherein p is 0
  • Q is -CH 2 -W, wherein W is selected from optionally substituted C -C 6 cycloalkyl, optionally substituted C -C 6 heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; and pharmaceutically acceptable salts thereof.
  • EP4 agonists ofthe invention for triggering ovulation for ovulation induction or ART include the following depicted compounds and pharmaceutically acceptable salts of these compounds: 4-(2- ⁇ (2R)-2-[(lE,3S)-3-hydroxy-4-phenylbut-l-enyl]-5-oxo ⁇ yrrolidin-l- yl ⁇ ethyl)benzoic acid; 4-(2- ⁇ (2R)-2-[(lE,3S)-4-(3-chlorophenyl)-3-hydroxybut-l-enyl]-5-oxopy ⁇ olidin-l- yl ⁇ ethyl)benzoic acid;
  • C ⁇ -C 6 -alky ⁇ refers to monovalent branched or unbranched alkyl groups having 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and the like.
  • C ⁇ -C 4 -alkyl refers to monovalent branched or unbranched alkyl groups having 1 to 4 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like.
  • C ⁇ -C 6 -heteroalkyl refers C ⁇ -C 6 -alkyl according to the definition above, in which at least one carbon atom is replaced by heteroatoms chosen from the group consisting of O, S, NR, R being defined as hydrogen or methyl.
  • Preferred C ⁇ -C 6 - heteroalkyl include methoxy methyl, methoxyethyl, methoxybutyl, and the like.
  • C 2 -C 6 -alkenyl refers to alkenyl groups preferably having from 2 to 6 carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation.
  • C 2 -C 6 -alkynyl refers to alkynyl groups preferably having from 2 to 6 carbon atoms and having at least 1-2 sites of alkynyl unsaturation, preferred alkynyl groups include ethynyl, (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), and the like.
  • C 2 -C 6 -heteroalkenyl and “C 2 -C 6 -heteroalkyny ⁇ ” refers respectively to C 2 -C 6 -allcenyl and C 2 -C 6 -alkynyl, in which at least one carbon atom is replaced by heteroatoms chosen from the group consisting of O, S, NR, R being defined as hydrogen or methyl.
  • Examples of C 2 -C 6 -heteroalkenyl include methoxy propenyl, methoxy butenyl, and the like.
  • Examples of C 2 -C 6 -heteroalkynyl include methoxy propynyl, methoxy butynyl, and the like.
  • C 3 -C 6 -cycloalkyl refers to saturated carbocyclic rings having 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and the like.
  • C 3 -C 8 heterocycloalkyl refers to a C 3 -C 8 -cycloalkyl group according to the definition above, in which up to 3 carbon atoms are replaced by heteroatoms chosen from the group consisting of O, S, NR, R being defined as hydrogen or methyl.
  • Preferred heterocycloalkyl include pyrrolidine, piperidine, piperazine, 1- methylpiperazine, morpholine, and the like.
  • C 3 -C 6 -cycloalkyl C ⁇ -C 6 -alkyl refers to d-C 6 -alkyl groups, as defined above, having saturated carbocyclic rings having 3 to 6 carbon atoms as substituent. Examples include ethyl cyclobutyl, cyclopropylmethyl cyclobutyl and the like.
  • Aryl refers to aromatic carbocyclic groups of from 6 to 14 carbon atoms having a single ring (e.g. phenyl) or multiple condensed rings (e.g. naphthyl). Examples include phenyl, naphthyl, phenanthrenyl and the like.
  • Aryl C ⁇ -C 6 -alkyl refers to Ci-C ⁇ -alkyl groups having an aryl substituent, including benzyl, phenethyl and the like.
  • ) / (R + S)
  • R represents the number of moles of R enantiomer in the sample and S represents the number of moles of S enantiomer in the sample
  • represents the Absolute Value of the difference of R and S.
  • Compounds of the invention can be obtained in an "Enantiomeric excess" by a synthesis comprising an enantioselective step or can be isolated by for example, crystallization or chiral HPLC.
  • a particularly preferred embodiment includes compounds of the invention in an enantiomeric excess of the S enantiomer, of at least at or about 50, 70, 80 or 90%, with degree of preference increasing with the increasing ee ofthe S enantiomer.
  • racemic products are usually obtained that do however also have the inventive set out activity as EP2 and/or EP4 agonists.
  • pro-drug refers to compounds that are drug precursors which, following administration, release the drug in vivo via some chemical or physiological process.
  • EP4 agonist refers to a compound, including its isomers, pro-drugs and pharmaceutically acceptable salts, which bind to prostaglandin E4 subtype receptor. Such property can be readily determined by those skilled in the art (for example, see Boie, Y. et al Eur. J. Pharmacol. 1997, 340, 227-241 or Abramovitz M. et al Biochim at Biophysica Acta 2000, 1483, 285-293). A variety of such compounds are described and referenced herein. However, other prostaglandin EP4 agonists will be known to those skilled in the art. Exemplary EP4 agonists are disclosed as follows.
  • selective binding to the EP4 receptor refers to compounds that are selective is in comparison to the other prostaglandin receptors, particularly EPl and/or EP3, optionally EP2.
  • Selectivity in this connection means that the affinity of the compounds of the invention for the EP4 receptor is at least more than 5 times higher than the affinity for EPl receptor and/or EP3 receptor, optionally EP2 receptor, especially more than 10 times and in particular more than 100 or 1000 times the affinity for other prostaglandin receptors like EPl or EP3 and at least more than 5 times, especially more than 10 times the affinity for the EP2 receptor.
  • fertility condition(s) also refers to a condition, particularly infertility, of a female mammal, especially a female patient. This condition includes conditions where ovulation triggering is needed. Examples of female patients in such a condition are female undergoing a treatment for ovulation induction or an Assisted Reproductive Technolo gy (ART) therapies .
  • ART Assisted Reproductive Technolo gy
  • OI ovulation induction
  • oocyte (occasionally two or three oocytes) into the fallopian tubes of a female patient, for in vivo fertilisation.
  • OI is used in anovulatory patients [for example, WHO group I patients (hypogonadotrophic hypogonadism) and WHO group II anovulation (hypothalamic-pituitary dysfunction resulting in arrested or attenuated gonadal function), including patients suffering from polycystic ovarian syndrome (PCOS)]. It is usually desired to stimulate the release of a single oocyte, in order to avoid the risks associated with multiple pregnancies.
  • a typical ovulation induction regimen the patient is administered FSH, an analogue of FSH or a molecule stimulating endogenous FSH production to stimulate follicular growth for several days until at least one follicle is observed (by ultrasound) with a mean diameter of approximately 17 mm or greater.
  • an ovulation trigger hCG
  • the molecules of the invention can replace or supplement the ovulation triggering dose of hCG in an OI regimen.
  • Assisted Reproduction Technology includes for example, in vitro fertilisation (INF), and intracytoplasmic sperm injection (ICSI).
  • Oocytes are harvested from mature follicles immediately before rupture, and graded before being fertilised in vitro by combination with sperm. The resulting embryos are graded for quality, and usually 2 to 3 are selected for placement in the uterus (remaining embryos can be cryopreserved for future attempts). Because of the many factors involved in establishing an ongoing pregnancy, many patients must have oocytes placed in the uterus multiple times before success is achieved. Because of this, in contrast to OI regimens, for ART it is desired to harvest multiple oocytes, in order to maximise the chances of successful pregnancy.
  • COH controlled ovarian hyper stimulation
  • hCG bolus Oocytes are usually recovered from pre-ovulatory follicles, by aspiration.
  • the molecules of the invention can replace or supplement the ovulation triggering dose of hCG in an ART regimen.
  • PVT polyvinyltoluene
  • PSS physiologic salt solution
  • RT room temperature
  • SPA Scintillation proximity Assay
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • TNF Tuour Necrosis factor
  • synthesis of the 15-hydroxy and 16-hydroxy ⁇ - lactam derivatives can be suitably obtained as outlined above using common intermediate (iv). That intermediate (iv) can be synthesized starting from the commercially available Glu derivative (i).
  • the amino groups can be suitably alkylated e.g. by reductive alkylation reaction using the appropriate aldehyde (e.g. a carboxyphenylacetaldehyde, like 4-carbomethoxyphenylacetaldehyde) and NaCNBH 3 or other suitable reducing agent.
  • the crude residue is then suitably refluxed in a suitable solvent such as xylene to afford the desired ⁇ -lactam derivative (ii).
  • Selective deprotection ofthe ester group directly attached to the ⁇ -lactam ring can be obtained by acid treatment (when H-D-Glu(O ? Bu)-O f Bu is used) or catalytic hydrogenation (when H- D-Glu(OBn)-OBn is used).
  • Reduction ofthe acid (iii) to the con-esponding alcohol (iv) can be accomplished by reduction e.g. with NaBH 4 of the correspondent acyl tert-butyl carbonate intermediate.
  • Synthesis of the 15-hydroxy derivatives of general formula (vii) can be suitably accomplished as follows.
  • Alcohol intermediate (iv) is suitably oxidized e.g. via Swern reaction to provide the desired aldehyde.
  • That aldehyde then can react with a suitable Wittig reagent particularly an appropriate diethyl 2-oxoalkylphosphonate (for synthesis of the phosphonate intermediate see J.Org.Chem. 1998, 63, 8894) to afford the alkene (v).
  • the ketone group then can be reduced e.g. using NaBH and CeCl 3 to afford the desired alcohol (vi). as a mixture of diastereoisomers. Reduction can proceed in high yields.
  • Chiral reduction of the enone intermediate can be accomplished in good yield and good diastereoselectivity by using (R)-2-methyl-CBS-oxazaborolidine reagent and BH 3 complexed with THF (J. Am. Chem. Soc. 1987, 109, 7925-7926) or other hydride reducing agent like N,N-diethylaniline borane (Org. Proc. Res. Dev. 2002, 6, 146-148) using THF or other suitable solvents. Saponification of the ester group e.g. using NaOH in MeOH/water/THF can provide desired product (vii).
  • ⁇ -Lactam derivatives having the hydroxyl group in position 16 can be suitably obtained by oxidation of the alcohol (iv) followed by Wittig reaction using the desired (3-hydroxyalkyl)(triphenyl)phosphonium salt (for synthesis of the phosphorane intermediate see Tetrahedron 1998, 54, 4243 or Chem.Lett. 1991, 113). Saponification ofthe ester group e.g. using NaOH in MeOH/water/THF can provide the desired product (ix).
  • Suitable protection of the primary alcohol is obtained by using TBDMSiCl, DMAP or other suitable catalyst, Et 3 N, in DMF or other suitable solvents. Protection of the secondary alcohol can be obtained by reaction of the pyrrolidinone derivative (xiii) with D ⁇ P, p-TsO ⁇ or other suitable acid catalysts. The pyrrolidinone derivative (xiv) could then be alkylated using propargyl bromide in the presence of a suitable base like K 2 CO and using as solvent acetone or other suitable solvents. Catalytic addition suitable halo-aryl esters can be accomplished using Cul and Pd (0) (Org. Lett. 2000, 2, 1729). Selective deprotection ofthe primary alcohol to afford intermediate (xvii) can be accomplished by using tetrabutyl ammonium fluoride or other suitable acid or nucleophilic reagents.
  • Alcohol intermediate (xvii) is suitably oxidized e.g. via Swern reaction to provide the desired aldehyde. That aldehyde then can react with a suitable Wittig reagent particularly an appropriate diethyl 2-oxoalkylphosphonate (for synthesis of the phosphonate intermediate see J.Org.Chem. 1998, 63, 8894) to afford the alkene (xviii).
  • a suitable Wittig reagent particularly an appropriate diethyl 2-oxoalkylphosphonate (for synthesis of the phosphonate intermediate see J.Org.Chem. 1998, 63, 8894) to afford the alkene (xviii).
  • the ketone group then can be reduced e.g. using NaBH and CeCl 3 to afford the desired alcohol (xix) as a mixture of diastereoisomers. Reduction can proceed in high yields.
  • Chiral reduction of the enone intermediate can be accomplished in good yield and good diastereoselectivity by using (R)-2-methyl-CBS-oxazaborolidine reagent and BH 3 complexed with THF (J. Am. Chem. Soc. 1987, 109, 7925-7926) or other hydride reducing agent like N,N-diethylaniline borane (Org. Proc. Res. Dev. 2002, 6, 146-148) using THF or other suitable solvents.
  • Acidic treatment e.g. HCl in MeOH
  • saponification of the ester group e.g. using NaOH in MeOH/water/THF can provide desired product (xx).
  • ⁇ -Lactam derivatives having the hydroxyl group in position 16 (xxi) can be suitably obtained as described in Scheme 4a below by oxidation of the alcohol (xvii) followed by Wittig reaction using the desired (3-hydroxyalkyl)(triphenyl)phosphonium salt (for synthesis of the phosphorane intermediate see Tetrahedron 1998, 54, 4243 or Chem.Lett. 1991, 113).
  • Acidic treatment e.g. HCl in MeOH
  • saponification of the ester group e.g. using NaOH in MeOH/water/THF
  • desired product xxii
  • the present invention includes methods for treating or preventing prostaglandin mediated or associated diseases or disorders.
  • Preferred therapeutic methods of the invention include inhibiting undesired smooth muscle contraction, including undesired prostanoid-induced smooth muscle contraction.
  • Methods of the invention include treatment of a patient suffering from or susceptible to dysmenorrhea, premature labor, asthma and other conditions that can be relieved by bronchodilation, inflammation, hypertension, undesired blood-clotting (e.g. to reduce or prevent thromboses) and other undesired platelet activities, preeclampsia and/or eclampsia and eosinophil-related disorders (eosinophil disorders).
  • Treatment and/or prevention of undesired blood clotting may include treatment and prophylaxis of venous thrombosis and pulmonary embolism, arterial thrombosis e.g. myocardial ischemia, myocardial infarction, unstable angina, stroke associated with thrombosis, and peripheral arterial thrombosis.
  • Compounds of the invention also may be useful for anticoagulation involving artificial organs, cardiac valves, medical implementation (e.g. an indwelling device such as a catheter, stent, etc.) and the like.
  • the invention also includes methods for treatment of infertility, which generally comprise administration of one or more pyrrolidine compounds of the invention to a mammal, particularly a primate such as a human, suffering from or suspected of suffering from infertility. See the Merck Manual, vol. 2, pages 12-17 (16 th ed.) for identification of patients suffering from or suspected of suffering from infertility, which in the case of humans, can include failure to conceive within one year of unprotected intercourse.
  • the treatment methods of the invention may be particularly beneficial for female mammals suffering from an ovulatory disorder.
  • compounds of the invention can be administered to females undergoing assisted reproductive treatments such as in-vitro fertilization, e.g. to stimulate follicular development and maturation, as well as implantation procedures.
  • treatment methods of the invention may be used in conjunction with in vitro fertilization technology to enhance survival and/or fertilization of a mammalian egg such as in INF setting.
  • Treatment methods ofthe invention also may be employed for control of cervical ripening in late pregnancy (e.g. in humans, late pregnancy would be third trimester, particularly week 30 onward).
  • Therapeutic methods of the invention also include treatment of glaucoma or other disorder involving elevated intra-ocular pressure.
  • Treatment methods ofthe invention also include inhibition or prevention of bone loss such as to treat osteoporosis, and for promoting bone formation (e.g. to use as a therapy in a bone fracture) and other bone diseases such as Paget's disease.
  • the invention also includes methods for treating a mammal that has low bone mass, or is susceptible to low bone mass such as a mammal having a condition that can present low bone mass, e.g. osteoporosis.
  • the invention also includes therapeutic methods for other bone mass augmentation treatments or enhancement, such as enhancing bone graft success rates or replacement of the need of such grafts, bone extension, bone healing following facial reconstruction and other treatments.
  • Such treatment also may be used in coordination with an appropriate medical device, such as an orthopedic device e.g. a spinal case, bone pins and screws, and other bone fixation devices.
  • such therapies are useful for any condition which can present low bone mass, which conditions include those where the level of bone mass is below the age specific normal as defined in standards by the World Health Organization "Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994), World Health Organization Technical Series 843.” More particularly, such conditions include periodontal disease, alveolar bone loss, post- osteotomy and childhood idiopathic bone loss, and primary and second osteoporosis as discussed above and complications thereof such as curvature of the spine, loss of height and prosthetic surgery.
  • Subject particularly suitable for such bone growth promotion therapies include subjects suffering from acute injuries that can involve bone damage, subjects having undergone related surgery such as facial reconstruction, and subjects that are at increased risk of the above discussed disorders and diseases such as post-menopausal women and men and women over the age of 50 or 60.
  • Compounds of the invention also will be useful to treat sexual dysfunction, including male sexual dysfunction, such as erectile dysfunction.
  • Compounds of the invention also are useful for treatment of a subject suffering from or susceptible to renal dysfunction, including a mammal suffering from or susceptible to acute or chronic renal failure. Such treatment methods can promote repair and/or regeneration of kidney tissue in a mammal, particularly a human.
  • Compounds of the invention also are useful for treatment of a subject suffering from or susceptible to an immune disorder including an immune deficiency disease or disorder, including such a disorder associated with a viral infection particularly a retroviral infection such as an HIN infection. Particularly benefited by such therapies will be a human suffering from or susceptible to AIDS.
  • Compounds ofthe invention will be further useful to reduce elevated intra-ocular pressure of a subject, e.g. through relaxation of pre-contracted isolated ciliary muscle.
  • a mammal such as a human suffering from or susceptible to glaucoma or other disorder associated with elevated intra-ocular pressure.
  • Compounds of the invention also will be useful for treatment of a mammal, particularly a human that is suffering from or susceptible to dry eye.
  • Compounds of the invention will be further useful for treatment of a subject suffering from or susceptible to inflammatory diseases or disorders, including vascular inflammation, inflammatory pain and hyperalgesia.
  • Compounds of the invention also will be useful for promoting sleep in a subject, e.g. to treat a mammal particularly a human suffering from or susceptible to a sleep disorder such as may be associated with advanced age, such as a human of 65 years or older.
  • the therapeutic methods of the invention generally comprise administration of an effective amount of one or more compounds ofthe invention to a subject including a mammal, such as a primate, especially a human, in need of such treatment.
  • Typical candidates for treatment in accordance with the methods ofthe invention persons suffering from or suspected of suffering from any of the above disorders or diseases, such as a female susceptible or suffering from preterm labor, or a subject suffering from or susceptible to dysmenorrhea or undesired bone loss.
  • the treatment methods of the invention also will be useful for treatment of mammals other than humans, including for veterinary applications such as to treat horses and livestock e.g. cattle, sheep, cows, goats, swine and the like, and pets such as dogs and cats. Methods of the invention to treat premature labor will be particularly useful for such veterinary applications. Therapeutic methods of the invention also will be useful for treatment of infertility in such veterinary applications.
  • a wide variety of mammals will be suitable subjects including rodents (e.g. mice, rats, hamsters), rabbits, primates and swine such as inbred pigs and the like.
  • rodents e.g. mice, rats, hamsters
  • rabbits primates and swine
  • primates and swine such as inbred pigs and the like.
  • body fluids e.g., blood, plasma, serum, cellular interstitial fluid, saliva, feces and urine
  • cell and tissue samples ofthe above subjects will be suitable for use.
  • Compounds of the invention including 1,2-substituted 5-pyrrolidinone compounds and EP4 agonists, may be administered as a "cocktail" formulation with other therapeutics, i.e.
  • one or more compounds of the invention may be administered in coordination for simultaneous, sequential or separate use, with a regime of a pain relief agent, an anti- inflammatory agent, or an anti-coagulant, depending on the indication being treated.
  • Suitable anti-coagulants for such coordinated drug therapies include e.g. warfarin, heparin, hirudin or hirulog or an antiplatelet such as ReoPro.
  • one or more compounds of the invention may be suitably administered in coordination, for simultaneous, sequential or separate use, with known fertility agents such as Follicle Stimulating and/or Leutinizing Hormone such as Gonal-F, Metrodin HP or Pergonal.
  • known fertility agents such as Follicle Stimulating and/or Leutinizing Hormone such as Gonal-F, Metrodin HP or Pergonal.
  • Compounds of the invention may be administered either as the sole active therapeutic or in a coordinated regime with one or more other therapeutics can be administered by a variety of routes, such as orally or by injection, e.g., intramuscular, intraperitoneal, subcutaneous or intravenous injection, or topically such as transdermally, vaginally and the like.
  • Pyrrolidine compounds of the invention may be suitably administered to a subject in the protonated and water-soluble form, e.g., as a pharmaceutically acceptable salt of an organic or inorganic acid, e.g., hydrochloride, sulfate, hemi-sulfate, phosphate, nitrate, acetate, oxalate, citrate, maleate, mesylate, etc.
  • a pharmaceutically acceptable salt of an organic or inorganic acid e.g., hydrochloride, sulfate, hemi-sulfate, phosphate, nitrate, acetate, oxalate, citrate, maleate, mesylate, etc.
  • base addition salts may be prepared. Lists of additional suitable salts may be found, e.g. in Part 5 of Remington 's Pharmaceutical Sciences, 20 th Edition, 2000, Marck Publishing Company, Easton, Pennsylvania.
  • Compounds of the invention can be employed, either alone or in combination with one or more other therapeutic agents as discussed above, as a pharmaceutical composition in mixture with conventional excipient, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, enteral or topical application which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof.
  • conventional excipient i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, enteral or topical application which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof.
  • Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc.
  • the pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • compositions of the invention may preferably include a compound of the invention, including a 1,2-substituted 5-pyrrolidinone compounds and EP4 agonists, packaged together with instructions (written) for therapeutic use of the compound to treat e.g. premature labor, dysmenorrhea or asthma, or other disorder as disclosed herein, such as a disease or disorder associated with or mediated by prostaglandin.
  • compositions containing one or more compounds of the invention may be formulated as e.g. tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixers and the like.
  • suitable are tablets, dragees or capsules having talc and/or carbohydrate carrier binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch.
  • a syrup, elixir or the like can be used wherein a sweetened vehicle is employed.
  • Sustained release compositions can be formulated including those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
  • the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
  • suitable are solutions, preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories.
  • Ampules are convenient unit dosages. It will be appreciated that the actual preferred amounts of active compounds used in a given therapy will vary according to the specific compound being utilized, the particular compositions formulated, the mode of application, the particular site of administration, etc.
  • a suitable effective dose of one or more 1,2-substituted 5-pyrrolidinone compounds of the invention will be in the range of from 0.01 to 100 milligrams per kilogram of bodyweight of recipient per day, preferably in the range of from 0.01 to 20 milligrams per kilogram bodyweight of recipient per day, more preferably in the range of 0.05 to 4 milligrams per kilogram bodyweight of recipient per day.
  • the desired dose is suitably administered once daily, or several sub- doses, e.g.
  • sub-doses are administered at appropriate intervals through the day, or other appropriate schedule.
  • Such sub-doses may be administered as unit dosage forms, e.g., containing from 0.05 to 10 milligrams of compound(s) of the invention, per unit dosage.
  • Examples 1 to 80 are preferred embodiments ofthe invention. Compounds from example 1 to 80 were synthesized according to scheme 1
  • Example l 4-(2- ⁇ (2R -2-r(lE,3S)-3-hydroxvoct-l-envll-5-oxopyrrolidin-l-yl ⁇ ethyl benzoic acid (first isomer in HPLC: ACN/H 2 O 0.1%TFA): 1H NMR (CD 3 OD) ⁇ 0.85- 0.95 (m, 3H), 1.20-1.50 (m, 8H), 1.65-1.81 (m, IH), 2.11-2.41 (m, 3H), 2.79-2.95 (m, 2H), 3.11-3.22 (m, IH), 3.65-3.80 (m, IH), 3.98-4.10 (m, 2H), 5.43 (dd, IH), 5.65 (dd, IH), 7.31 (d, 2H), 7.94 (d, 2H); MS (m/z) 360 (M+l).
  • Example 2 4-(2- ⁇ (2R -2-r(lE,3R)-3-hydroxvoct-l-enyl1-5-oxopyrrolidin-l-yl ⁇ ethyl) benzoic acid (second isomer in HPLC: ACN/H 2 O 0.1% TFA): 1H NMR (CD 3 OD) ⁇ 0.85-0.95 (m, 3H), 1.20-1.55 (m, 8H), 1.65-1.78 (m, IH), 2.11-2.45 (m, 4H), 2.80-2.95 (m, 2H), 3.16-3.28 (m, IH), 3.65-3.80 (m, IH), 3.98-4.10 (m, 2H), 5.43 (dd, IH), 5.70 (dd, IH), 7.33 (d, 2H), 7.94 (d, 2H); MS (m/z) 360 (M+l).
  • Example 4 4-(2-
  • Example 5 4-(2- ⁇ 2-[(lE,3S)-3-hydroxy-4,4-dimethyloct-l-enyl]-5-oxopyrrolidin-l- yl ⁇ ethyl)benzoic acid: (First isomer in HPLC: ACN/H 2 O/TFA, 30 mg): 1H NMR (CDC1 3 ): ⁇ 0.76-0.
  • Examples 7 and 8 Synthesis of 4-(2- ⁇ (2R)-2-[(lE,3R)-3-hydroxy-3-(l- phenylcyclopropyI)prop-l-enyl]-5 oxopyrrolidin-l-yl ⁇ ethyl)benzoic acid and 4-(2- ⁇ (2R)-2-[(lE,3S)-3-hydroxy-3-(l-phenylcyclopropyI)prop-l-enyl]-5-oxopyrrolidin- l-yl ⁇ ethyl)benzoic acid
  • Example 7 4-f 2- ((2RV 2- ⁇ ( 1E.3RV3 -hvdroxv-3 -(1 -phenylcyclopropypprop- 1 -enyll -5 oxo pyrrolidin-l-yl ⁇ ethyl)benzoic acid (First isomer in HPLC: ACN/H 2 O 0.1% TFA) 1H NMR (D 2 O) ⁇ 0.75-0.93 (m, 4H), 1.45-1.63 (m, IH), 2.00-2.12 (m, IH), 2.20-2.35 (m, 2H), 2.78-2.90 (m, 2H), 3.05-3.12 (m, IH), 3.60-3.78 (m, 2H), 3.81-3.90 (m, IH), 5.25 (dd, IH), 5.50 (dd, IH), 7.20-7.40 (m, 7H), 7.76 (d, 2H); MS (m/z) 406 (M+l).
  • Example 8 4-(2-((2E -2-rriE,3S)-3-hvdroxy-3-(l-phenvlcvclopropyl)prop-l-envll-5- oxo pyrrolidin-l-yl ⁇ ethyl)benzoic acid (Second isomer in HPLC: ACN/H 2 O 0.1% TFA).
  • Example 9 4-(2- ⁇ (2R)-2-[(l£,3S)-3-hydroxy-4-(3-chlorophenyl)but-l-enyl]-5- oxopyrro lidin-l-yl ⁇ ethyI)benzoic acid.
  • Example 10 4-(2- ⁇ (2R)-2-[(IE,3S)-3-hydroxynon-l-enyl]-5-oxopyrrolidin-l- yl ⁇ ethyl) benzoic acid.
  • Example 11 4-(2- ⁇ (2R -2-f3-(3S)-hydroxynonyl]-5-oxopyrrolidin-l-yl ⁇ ethyl) benzoic acid.
  • Example 16 4-[2- ⁇ (2R)-2-[(lE, 3S)-3-hydroxyhept-l-enyl]-5-oxopyrrolidin-l- yl ⁇ ethyl) benzoic acid.
  • Example 16 4-[2- ⁇ (2R)-2-[(lE, 3S)-3-hydroxyhept-l-enyl]-5-oxopyrrolidin-l- yl ⁇ ethyl) benzoic acid.
  • Example 18 4- ⁇ 2-((2R)-2- .(lEs 3S)-3-ri-(4-chloiOphenvPcvclopentvll-3-hydroxyprop- l-enyl ⁇ -5-oxopyrrolidin-l-yl)ethyl]benzoic acid (the second isomer in RP-HPLC:
  • Example 29 4-(2- ⁇ (2R)-2-[(iE,3S)-3-hydroxy-6-methoxyhex-l-enyl]-5-oxo pyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 29 4-(2- ⁇ (2R)-2-[(2E,3S)-3-hydroxy-6-methoxyhex-l-enyl]-5- oxopyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 30 4-(2- ⁇ (2R)-2-[(lE,3S)-3-hydroxy-4-cyclohexyl-but-l-enyl]-5-oxo pyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 30 4-(2- ⁇ (2R)-2-[(lE,3S)-3-hydroxy-4-cyclohexyl-but-l-enyl]-5- oxopyrr olidin-1 -yl ⁇ ethyl)b enzoic acid.
  • Example 31 4-[2- ⁇ (2R)-2-[(lE, 3S)-3-hydroxy-4-phenylbut-l-enyI]-5-oxopyrrolidin- l-yl ⁇ ethyl)benzoic acid.
  • Example 31 4-[2- ⁇ (2R)-2-[(lE, 3S)-3-hydroxy-4-phenylbut-l-enyl]-5-oxopyrrolidin- l-yl ⁇ etkyI)benzoic acid.
  • Example 32 4-[2- ⁇ (2R)-2-[(lE, 3S)-3-hydroxy-oct-l-en-7-nyyl]-5-oxopyrrolidin-l- yl ⁇ ethyl)benzoic acid.
  • Example 32 4-[2- ⁇ (2R)-2 ⁇ [(LE, 3S)-3-hydroxy-oct-l-en-7-nyyl]-5-oxopyrrolidin-l- yl ⁇ ethyl)benzoic acid.
  • Example 33 4-[2- ⁇ (2R)-2-[(lE, 3S)-5,5-dimethyl-3-hydroxyhex-l-enyl]-5-oxo pyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 33 4-[2- ⁇ (2R)-2-[(LE, 3S)-5,5-dimethyl-3-hydroxyhex-l-enyl]-5- oxopyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 34 4-[2- ⁇ (2R)-2-[(lE, 3S)-5-methyl-3-hydroxyhex-l-enyl]-5-oxopyrrolidin- l-yl ⁇ ethyl)benzoic acid.
  • Example 35 4-[2- ⁇ (2R)-2-[(lE, 3S)-7-chloro-3-hydroxyhept-l-enyl]-5- oxopyrrolidin-l-yl ⁇ ethyI)benzoic acid.
  • Example 35 4-[2- ⁇ (2i?)-2-[(lE, 3S)-7-chloro-3-hydroxyhept-l-enyl]-5- oxopyrrolidin-1 -yl ⁇ ethyl)b enzoic acid.
  • Example 36 4-[2- ⁇ (2i?)-2-[(lE, 3S)-3-hydroxy-oct-l-enyl]-5-oxopyrrolidin-l- yl ⁇ ethyl)b enzamide.
  • Example 40 4- ⁇ 2-[(2R)-2((lE-3R,7R)-3,7-dihydroxyoct-l-enyl)-5-oxopyrrolidin-l- yl ⁇ ethyl ⁇ benzoic acid.
  • Example 41 and 42 4- ⁇ 2-[(2R)-2((lE,7S)-3,7-dihydroxyoct-l-enyl)-5-oxo pyrrolidin-l-yl ⁇ ethyl ⁇ benzoic acid.
  • Intermediate 41.6 (96 mg, 0.247 mmol) was dissolved in MeOH/THF/H 2 O (1/1/1 mL) and added NaOH (1.0 M, 0.62 mL, 0.62 mmoL). The mixture was stirred for overnight. The residue was purified through RP-HPLC using ACN and H 2 O/0.1%TFA to afford Example 41 (130 mg) and example 42 (32 mg) as a white solid.
  • Example 43 4-(2- ⁇ (2R)-3-(3R)-hydroxy-4 ⁇ methyl-4-phenylpentyl]-5-oxopyrrolidin- l-yl ⁇ ethyl)benzoic acid.
  • Intermediate 43.1 (0.474 mmol) was dissolved in MeOH/THF/H 2 O (2/2/2 mL) and added NaOH (1.0 M, 0.1.20 mL, 1.20 mmoL). The mixture was stirred for overnight. The residue was purified through RP-HPLC using ACN and H2O/O.P/0TFA to afford Example 43 (88 mg) as a white solid.
  • Example 45 and 46 Synthesis of: 4-(2- ⁇ (2R) ⁇ 2-[(lE)-3-(l-butylcyclobutyl)-3- hydroxyprop-l-enyl]-5-oxopyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 45 and 46 4-(2- ⁇ (2R)-2-[(lE)-3-(l-butylcyclobutyl)-3-hydroxyprop-l- enyl] -5-oxopyr rolidin-1 -yl ⁇ ethyl)benzoic acid.
  • This intermediate was synthesized using the procedure of Example 1 and 2 from intermediate 45.5.
  • Example 47 and 48 Synthesis of 4-(2- ⁇ (2R)-2-[(lE)-3-hydroxy-3-(l -propyl cy clobut l)prop-l -eny 1] -5-oxopyrr olidin-1 -yl ⁇ ethyl)b enzoic acid.
  • Example 49 Synthesis of 4-(2- ⁇ (2R)-2-[(lE, 3R)-3-(l-benzylcyclobutyl)-3- hydroxyprop-l-enyl]-5-oxopyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 50 and 51 Synthesis of 4-[2-((2R)-2- ⁇ (lE)-3-hydroxy ⁇ 3-[l-(2- phenylethyl)cyclobutyl]prop-l-enyl ⁇ -5-oxopyrrolidin-l-yl)ethyl]benzoic acid.
  • Example 52 Synthesis of 4-(2- ⁇ (2R)-2-[(lE,3S)-3-hydroxy-5-phenylpent-l-enyl]-5- oxopyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 53 Synthesis of 4-(2- ⁇ (2R)-2-[(lE,3S)-3-hydroxy-4-(3-methylphenyl)but- 1 -enyl] -5-oxopyrrolidin-l -yl ⁇ ethyl)b enzoic acid.
  • Example 53 was prepared using the procedure of Example 9 from ethyl m- tolylacetate.
  • Example 54 Synthesis of 4-(2- ⁇ (2S)-2-[(3R)-3-hydroxy-4-(3-methylphenyl)butyl]-5- oxopyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 54 was prepared using the procedure of Example 53 from ethyl m- tolylacetate.
  • Example 56 and 57 Synthesis of 4-[2-((2R)-2- ⁇ (lE)-3-[l-(4-chlorophenyl) cyclopropyl] -3-hy droxypr op-1 -enyl ⁇ -5-oxopy rr olidin-1 -yl) ethyl] b enzoic acid.
  • Example 56 and 57 were prepared using the procedure of Example 45 and 46 from l ⁇ (4-chlorophenypcyclopropanecarboxylic acid.
  • Example 58 and 59 Synthesis of 4-(2- ⁇ (2R)-2-[(lE)-4-(4-chlorophenyl)-3-hydroxy- 4-methylpent-l-enyl]-5-oxopyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 58 and 59 were prepared using the procedure of example 45 and 46 from 2-(4-chlorophenyl)-2-methylpropanoic acid.
  • Example 60 and 61 Synthesis of 4-(2- ⁇ (2R)-2-[(lE)-4-cyclopropyl-3-hydroxybut-l- enyl]-5-oxopyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 60 and 61 were prepared using the procedure of Example 45 and 46 starting from cyclopropylacetic acid.
  • Example 62 and 63 Synthesis of 4-(2- ⁇ (2R)-2-[(lE)-4-cyclopentyl-3-hydroxybut-l- enyl]-5-oxopyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 62 and 63 were prepared using the procedure of example 45 and 46 starting from cyclopentylacetic acid.
  • Example 64 Synthesis of 4-(2- ⁇ (2R)-2-[(lE)-4-hydroxyoct-l-enyl]-5-oxopyrrolidin- l-yl ⁇ ethyl)benzoic acid.
  • Example 64 4-f 2- If 2RV2-[(1 E)-4-hydroxyoct- 1 -enyll-5-oxopyrrolidin- 1 -yl ⁇ ethyl) benzoic acid.
  • Example 65 4-[2-rr2R)-2- ⁇ (lE,3R)-3-ri-rcvclopropvlmethvPcvclobutyll-3- hydroxyprop -l-enyl ⁇ -5-oxopyrrolidin-l-yl)ethyl]benzoic acid (first isomer in HPLC: ACN/H 2 O/TFA): 1H NMR (CD 3 OD) ⁇ 0.01-0.12 (m, 2FI), 0.45-0.49 (m, 2H), 0.73-0.83 (m, IH), 1.32-1.48 (m, 2H), 1.69-1.91 (m, 4H), 1.99-2.08 (m, 2H), 2.13-2.22 (m, IH), 2.27-2.42 (m, 2H), 2.74-2.93 (m, 2H), 3.07-3.16 (m, IH), 3.71-3.80 (m, IH), 3.92-3.99 (m, IH), 4.12-4.17 (m, IH), 5.
  • Example 67 Synthesis of: 4-(2- ⁇ (2R)-2-[(lE,3S)-3-hydroxypent-l-enyl]-5-oxo pyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 68 Synthesis of: 4-(2- ⁇ (2R)-2-[(lE,3S)-3-hydroxyhex-l-enyl]-5-oxo py rrolidin-1 -yl ⁇ ethyl)b enzoic acid.
  • Example 69 Synthesis of: 4-(2- ⁇ (5R)-2-oxo-5-[(lE,3S)-6,6,6-trifluoro-3-hydroxyhex- l-enyl]pyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 70 Synthesis of: 4-(2 ⁇ (2R)-2-[(lE,3S)-3-hydroxy-6-methylhept-l-enyl]-5- oxopyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 71 Synthesis of: 4-(2- ⁇ (2R)-2-[(lE,3S)-6-cyclopropyI-3-hydroxyhex-l- enyl] -5-oxopy rrolidin-1 -yl ⁇ ethyl)b enzoic acid.
  • Example 72 Synthesis of: 4-(2- ⁇ (2R)-2-[(lE,3R)-4-(allyIoxy)-3-hydroxybut-l-enyl]- 5-oxopyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 72 4-(2- ⁇ r2R)-2-r(lE,3R)-4-(allvloxy -3-hvdroxybut-l-enyll-5-oxopyrrolidin- 1-yl ⁇ ethyPbenzoic acid: This compound was synthesized from intermediate 1.4 and intermediate 71.1 following the procedure described for example 9.
  • Example 73 Synthesis of: 4-(2- ⁇ (2R)-2-[(lj-?,3R)-3-hydroxy-4-phenoxybut-l-enyl]-5- oxopyrrolidin-l ⁇ yl ⁇ ethyl)benzoic acid.
  • Example 74 Synthesis of 4-(2- ⁇ (2R)-2-[(lE)-3-hydroxy-3-methyloct-l-enyl]-5- oxopyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 74 4-(2- ⁇ (2R)-2-[(lE)-3-hydroxy-3-methyloct-l-enyl]-5-oxopyrroIidin-l- yl ⁇ ethyl) benzoic acid.
  • Example 75 and 76 Synthesis of 4-(2- ⁇ (2i?)-2-[(lE -3-hydroxy-5-methoxypent-l- enyl] -5-oxopy rrolidin-1 -yl ⁇ ethy l)b enzoic acid.
  • Example 75 (first isomer in RP-HPLC; ACN/H2O 0.1% TFA): l ⁇ i -NMR (CD 3 OD) ⁇ 1.60-1.85-(m, 3H), 2.08-2.20 (m, IH), 2.26-2.42 (m, 2H), 2.80-2.93 (m, 2H), 3.10-3.21 ( , IH), 3.42-3.55 (m, 2H), 3.65-3.75 (m, IH), 3.90-4.00 ( , IH), 4.15-4.22 (m, IH), 5.37 (dd, IH), 5.54 (dd, IH), 7.28 (d, 2H), 7.80 (d, 2H); MS (m/z) 348 (M+l).
  • Example 76 (second isomer in RP-HPLC; ACN/H2O 0.1% TFA): 1H-NMR (CD 3 OD) ⁇ 1.60-1.85 (m, 3H), 2.05-2.20 (m, IH), 2.22-2.42 (m, 2H), 2.80-2.93 (m, 2H), 3.16-3.27 (m, IH), 3.42-3.58 (m, 2H), 3.60-3.75 (m, IH), 3.88-3.97 (m, IH), 4.15-4.22 (m, IH), 5.33 (dd, IH), 5.57 (dd, IH), 7.28 (d, 2H), 7.82 (d, 2H); MS (m/z) 348 (M+l).
  • Example 77 Synthesis of 4-(2- ⁇ (2R)-2-[(lE,3S)-3-hydroxyhepta-l,6-dienyl]-5- oxopyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 78 Synthesis of 4-(2- ⁇ (2R)-2-[(lE)-3-hydroxy-5-morpholin-4-ylpent-l- enyl]-5-oxopyrrolidin-l-yl ⁇ ethyl)benzoic acid.
  • Example 79 4- ⁇ 2-[(2R)-2((lE,3R)-5-cyclopentyl-3-hydroxypentyl-l-enyl)-5- oxopyrro lidin-l-yl ⁇ ethyl ⁇ benzoic acid.
  • Example 80 4- ⁇ 2- [(2i?)-2((lE,3R)-3-hydroxy-7-methyloct-l -enyl)-5-oxopyrroIidin- l-yl ⁇ ethyl ⁇ benzoic acid.
  • EP2 receptor binding assay designates the following protocol.
  • EXAMPLE 82 EP2 cAMP assay. Compounds of the invention were tested in a total cAMP assay as follows.
  • HEK293-EBNA cells transfected with pCEP4-hEP2 receptors were seeded in 96 well opaque plate (Costar #3917) at 4xl0 4 cells per well in 100 ⁇ l of culture medium (D- MEM/F12 supplemented with 10% FBS, 2 nM L-glutamine, and 250 ⁇ g/ml of hygromycin; all from GibcoBRL) and incubated at 37°C. After overnight incubation, the medium was removed from each well and replaced with 45 ⁇ l of assay medium consisted of phenol red free D-MEM/F-12, 0.1 % BSA (GibcoBRL) and 0.1 mM3- isobutyl-1-methyl-xanthine (Sigma).
  • EXAMPLE 84 EP4 cAMP assay.
  • HEK293-EB ⁇ A cells transfected with pCEP4-hEP4 receptors were seeded in 96 well opaque plate (Costar #3917) at 4xl0 4 cells per well in 100 ⁇ l of culture medium (D- MEM/F12 supplemented with 10% FBS, 2 nM L-glutamine, and 250 ⁇ g/ml of hygromycin; all from GibcoBRL) and incubated at 37°C.
  • Results ofthe assays of Examples 81, 82, 83 and 84 are set forth in the following Table 1 wherein the tested compound is identified both by the corresponding synthetic Example number above as well as structure ofthe tested compound. Table 1:
  • EXAMPLE 85 In vivo ovulation assay: Ovulation triggering activity of compounds of the invention are tested in a mature mouse ovulation induction model.
  • Test compound is then diluted with saline or other diluents such as PBS or NP3S (5% N-methyl-pyrrolidinone/30% PEG-400/25% PEG-200/20% Propylene Glycol in saline).
  • PMSG serves to stimulate follicule growth and maturation. Mature follicules will ovulate when an ovulation triggering dose of hCG or an hCG replacement is administered.
  • test protocol was employed for the test animals (typically 5 animals per test group).
  • the compounds of the invention for evaluating the oral activity of this compound, two experiments were conducted, the first experiment was conducted with non-fasted animals and the second experiment was conducted in 24 h fasted animals (water provided).
  • the compounds of the invention according to their solubility are pre-dissolved in ethanol, DMSO or other reagents.
  • the compounds of the invention are then diluted with saline or other diluents such as PBS or NP3S before oral administration.
  • Compound of example 1 is submitted to different testing in the in vivo ovulation induction model as described above in order to assess its ability to trigger ovulation via subcutaneous (sc), oral (po) and intravenous (iv) routes of administration.
  • sc subcutaneous
  • po oral
  • iv intravenous
  • Group 2 an average of 19.4 ova were obtained for Group 3; an average of 25 ova were obtained for Group 4; an average of 22.4 ova were obtained for Group 5; and an average of 25.2 ova were obtained for Group 6.
  • test compound used by s.c. injection with Groups 4, 5 and 6 was 4-(2- ⁇ (2R)-2-[(lE)-3-hydroxyoct-l-enyl]-5-oxopyrrolidin-l-yl ⁇ ethyl)benzoic acid (compound of Example 1 above).
  • Compound of example 1 was found active in the mice ovulation induction model via subcutaneous (sc), oral (po) and intravenous (iv) routes of administration.
  • the calculated ED 50 for compound 1 in non- fasted animals is 21.97 mg/kg ( Figure 2).
  • ED 5 o is 21.1 mg/kg.
  • EP4 agonists are selected as described in Examples 83 and/or 84 on the basis of their Ki and/or EC 50 values.
  • EP4 selective agonists are the following: 4-(2- ⁇ 2-[4-(3-iodophenyl)-3-hydroxybutyl]-5-oxopyrazolidin-l-yl ⁇ ethyl)benzoic acid whose Ki value was measured as described in Example 83 is 14 nM (Ki on EP2 being 4450nM) induces the release of 10 ⁇ 3 ova when administered orally at the single dose of 20 mg/kg in the ovulation induction model decribed above.
  • EXAMPLE 86 In vivo inhibition of Guinea Pig broncho-constriction.
  • Guinea pig pulmonary-cholinergic in vivo model is generally used to test the materials for the treatments of asthma in human (Fleisch at al. 1985, K. Pharmacol. Exp. Ther. 233: 148-157). Compounds ofthe invention are tested in this model.
  • Groups of 3 Duncan Hartley derived male or female guinea pigs weighing 250 + 50 g are anesthetized with pentobarbital sodium (50 mg/kg i.p., plus an additional 15 mg/kg i.p. if required) and succinylcholine chloride (2 mg/animal i.p.) is subsequently administered to prevent spontaneous respiration. Body temperature is maintained at 37° to 38°C.
  • the trachea is cannulated and the guinea pig is ventilated with a Harvard rodent respirator in a closed system. Tracheal pressure is recorded through a side-arm of the cannula connected to a P23ID Statham transducer. Respiratory rate is set at 50 strokes/minute with a stroke volume (approximately 1 ml/100 g) sufficient to produce a baseline tracheal pressure of 6 cm H 2 O.
  • Mean arterial pressure (BP) is monitored from a cannulated carotid artery, and heart rate (HR) is obtained from chest electrodes arranged for lead II.
  • the jugular vein is cannulated for i.v. vehicle or drug administration in a volume of 1 ml/kg.
  • compound of the invention reference compound or vehicle is administered IT 10 (5 min for experiment 1 and 2) minutes before methacholine chloride (10 ⁇ g/kg i.v.) induced bronchoconstriction.
  • IT 10 methacholine chloride (10 ⁇ g/kg i.v.) induced bronchoconstriction.
  • Tracheal pressure (ITP) blood pressure and heart rate are measured immediately as indicated in the material and methods sections.
  • MED medium effective dose
  • a 50 percent or greater (>50%) inhibition of the induced bronchoconstriction relative to vehicle treated control animals is considered significant.
  • Compounds of the invention are administered i.v. (10 mg/kg) 5 minutes before subministration of the methacoline hydrochloride challenge in 3 guinea pigs. A 50 percent or more ( 50) inhibition of the induced bronchoconstriction relative to vehicle freated control animals is considered significant.
  • Compounds of the invention show an activity in dilation of bronchiolar muscles, which resulted in inhibition of methacholine-induced bronchomuscle constriction.
  • EXAMPLE 87 In vivo inhibition of LPS-induced TNFa release in mice.
  • Prostaglandin E2 is suggested to be an endogenous inhibitor of inflammation through the EP4 receptor. Therefore EP2 and/or EP4 agonists are suppoed to have an anti-inflammatory activity.
  • Endotoxins are the lipopolysaccharides (LPS) constituents ofthe outer membrane of Gram negative bacteria. Response to LPS has been shown to involve the activation of different cell populations and to lead to the expression of various inflammatory cytokines that include tumor necrosis factor-alpha (TNF ⁇ ) and interferon gamma (IFN- ⁇ ).
  • TNF ⁇ tumor necrosis factor-alpha
  • IFN- ⁇ interferon gamma
  • the anti-inflammatory activity of compounds ofthe invention may be assessed after a LPS challenge using the following protocol:
  • mice Eight weeks old C3H/HEN mice (IFFA-CREDO, L'avesle, France) receive an oral freatment with compounds ofthe invention 6 different doses (0.001, 0.01, 0.1, 1 or 3 and 10 mg/kg in 0.5% CMC/0.25% tween-20).
  • Six mice are used by group.
  • endotoxins (Olll:B4 Sigma, 0.3 mg/kg) are intraperitoneally injected. Heparinized whole blood is collected by decapitation. TNF ⁇ level is determined in plasma by ELISA (R & D Systems, Abdingdon, UK).
  • Control animals receive 0.5% CMC/0.25% tween-20 (10 ml/kg) as vehicle. Data obtained from experiments are expressed as the mean ⁇ SEM and analysed using one-way analysis of variance (ANOVA) followed by Dunnett's t-test.
  • ANOVA analysis of variance
  • the activity ofthe compounds ofthe invention is expressed as a percentage of inhibition of TNF release and the Inhibitory Dose at 50% ofthe maximum effect (ID50) is calculated in mg/kg. Data are presented in Table 4 below: Table 4
  • the data show that the compounds ofthe invention are able to inhibit the release of TNF alpha in a LPS-challenge model.
  • EXAMPLE 88 In vivo effect on penile corpus cavernosum tissue relaxation.
  • Penile erection is based on three main physiological events: an increase in the • arterial blood flow, a relaxation ofthe expansive tissue ofthe corpora carvernosa abd the corpus spongiosum, and an obstruction of the venous return by mechanicak compression ofthe veins caused by the expansive tissue.
  • PGEl is used in the treatment of erectile dysfunction to relax smooth muscle and therefore to promote the development of erection.
  • the administration of PGEl is performed by local injection into the cavernous tissue ofthe penis.
  • PGEl has a low selectivity for prostanoid receptors and has irritant effects.
  • Selective agonists EP2 and/or EP4 have been developed for the treatment of erectile dysfunction (WO 9902164)
  • Cavernosal tissue is obtained from patients undergoing penile prosthesis implantation surgery for treatment of erectile dysfunction.
  • biopsies of the corpora cavernosa are immediately placed in chilled (4°C) physiologic salt solution and transported to the laboratory.
  • Tissue strips measuring approximately 3 mm x 3 mm x 10 mm, are cut and prepared for organ bath studies.
  • Rabbit tissue procurement Adult male New Zealand White rabbits (4.5 - 5.0 kg) are sedated with ketamine (35 mg/kg) and xylazine (5 mg/kg) and euthanized with sodium pentobarbital (60 mg/kg body weight). Following exsanguination, the penis is excised and cleaned by removing the corpus spongiosum and urethra. Corpus cavernosum tissue strips are dissected away from the surrounding tunica albuginea and prepared for organ bath studies.
  • the solution is gassed with 95% air / 5% CO 2 to attain a pH of 7.4 and the temperature is maintained at 37°C.
  • All tissue strips are treated with 3 ⁇ M indomethacin to inhibit endogenous prostanoid production and minimize spontaneous contractile activity.
  • the corpus cavernosum tissue is stretched incrementally and the optimal resting isometric tension for contraction is determined. After every 3 - 4 stretches (1 g tension/stretch), the tissue is contracted with 1 ⁇ M phenylephrine. When the amplitude of the phenylephrine-induced contraction is within 10% of the previous contraction, that tension is considered optimal for isometric contraction.
  • All tissue strips are extensively washed with fresh PSS. Tissue strips are then contracted with 1 ⁇ M phenylephrine. After stable tone is achieved, tissue strips are exposed to increasing concentrations of PGEi or compounds ofthe invention.
  • EXAMPLE 89 In vivo effect on bone loss prevention.
  • the activity of compounds of the invention as a bone anabolic agent can be tested for example in a rat ovariectomy model such as follows.
  • Virgin female Sprague Dawley rats are randomized into treatment groups based on pre-dose body weight measurements. The aim iss to achieve approximately the same average body weight for every treatment group.
  • the ovary is located and cut at the junction ofthe uterine horn and removed.
  • the uterus is replaced and the muscles sutured. Repeat on the contra-lateral side.
  • the ovaries are located and exteriorized, but not removed.
  • the uterus and ovaries are replaced into the abdominal cavity and the muscles sutured.
  • the muscle layers are closed with suture and the skin incision closed using wound clips.
  • Dosing is commenced one day after the surgery is performed.
  • the animals receive daily subcutaneous injections for 6 weeks following surgery.
  • the doses of 0.1, 1.0, 10.0 mg/kg of compounds ofthe invention are used.
  • a control group receives daily subcutaneous injections of 17 ⁇ estradiol (Sigma Chemicals) of 30 ⁇ g/kg for 6 weeks following surgery.
  • Control groups of animal are injected s.c. vehicle (saline).
  • Body weights are recorded weekly, beginning one week prior to the commencement of treatment and continuing until the conclusion ofthe treatment period.
  • the rats are observed daily for signs of ill health or reaction to treatment.
  • An eighteen-hour urine specimen is collected from each animal prior to the sacrifice using metabolic cages. At sacrifice, blood samples are collected from each rat, under inhalation anesthesia (ether) from the retro-orbital sinus. Following parameters are measured in urine and serum.
  • ether inhalation anesthesia
  • Urinary deoxypyridinoline is measured by Immuno-assay (Pyrilinks-D Quidel, Mt. View,CA); Urinary creatinine is measured by COB AS chemistry instrument (Creatinine Reagent Roche Diagnostics, Indianapolis, IN); Serum osteocalcin is measured by Immuno-assay (Rat OSU IRMA, Immunotopics San Clemente, CA)
  • Necropsy Upon completion of dosing and urine/blood collection, animals are euthanized using carbon dioxide asphyxiation.
  • L2-L4 lumbar vertebrae is subjected to DXA (Dual-energy X-ray absorptiometry) scan using a PlXhnus instrument (Lunar Corp. Madison, WI). Bone mineral content, area and density are determined from the PIXI scan. Bone mineral density measurements by DXA are described in Formica et al. 1998, Osteoporosis International, 8 (5), 460-467.
  • Right femur is subject to pQCT (peripheral quantitative computed tomography) scan using a Stratec XCT RM and associated software (Stratectechnik Gmbh, Pforzheim, Germany. Software version 5.40 C).
  • the femur is scanned at two sites, 20% ofthe distal femur and 50%) ofthe mid-femur. The position is verified using scout views and scan results from one 0.5 mm slice perpendicular to the long axis ofthe femur shaft is recorded.
  • Total bone mineral content, total bone area, total bone mineral density, trabecular bone mineral content, trabecular bone area and trabecular bone mineral density are analyzed from the scan of the distal femur.
  • total bone mineral content, total bone area, total bone mineral density, cortical bone mineral content, cortical bone area, cortical bone mineral density, periosteal perimeter and endosteal perimeter are analyzed. Bone mineral density measurements by pQCT are described in Formica et al.
  • L5 Lumbar vertebra is isolated from L5-L6 and prepared for mechanical testing by removing the vertebral arch and pedicle using a low-speed diamond saw. The cranial and caudal ends of each vertebral body are also removed to produce a vertebral body specimen with two parallel surfaces and a height of approximately 4 mm. The width of the vertebral body in the medial-lateral and anterior-posterior directions is measured using electronic digital calipers. These values are recorded and used in the calculation of cross-sectional area. The height of the vertebral body specimen is also taken with an electronic caliper and recorded.
  • the load is applied at a constant displacement rate of 6 mm min until the femur breaks.
  • the locations of maximal load, stiffness and energy absorbed are selected manually and values calculated by instrument's software (Merlin II, Instron).
  • the intrinsic properties, stress, elastic modulus and toughness are calculated from maximum load, stiffness, energy absorbed, anterior-posterior diameter, and moment of inertia.
  • a 3 -mm segment of the distal femoral metaphysis is cut directly proximal to the femoral condyle with a low-speed diamond saw.
  • the load is applied with a cylindrical indenter (with a flat testing face of 1.6 mm diameter (d)) to the center of marrow cavity on the distal face of the segment.
  • the indenter is allowed to penetrate the cavity at a constant displacement rate of 6 mm/min to a depth of 2 mm before load reversal.
  • the locations of maximum load, stiffness and energy absorbed is selected manually from load displacement curve and then calculated by the instrument's software (Merlin II, Instron). Stress is calculated by dividing the maximum load by the indenter area.
  • proximal tibia Formalin-fixed samples of proximal tibia are dehydrated in a series of ascending ethanol concentration. Following dehydration, bone samples are infiltrated and embedded in methyl methacrylate-based plastic. Embedded samples of the proximal tibia are sectioned longitudinally using a Leitz motorized rotary microtome equipped with a tungsten-carbide microtome knife. Once the blocks are trimmed, 4 ⁇ m sections are stained with Goldner's trichrome stain for microscopy. The 8 ⁇ m sections are left unstained for epifluorescence microscopy.
  • Histomorphometric determinations Static and dynamic histomorphometry of the proximal tibia is performed.
  • the measurement includes the secondary spongiosa (area that is 1.05 from the lowest point ofthe growth plate).
  • Bone histomorphometry is performed using an OsteoMeasure software program (OsteoMetrics, Inc. Atlanta, GA) interfaced with a Nikon Eclipse E400 light/epifluorescent microscope and video subsystem. Histomorphometry is read in a blinded manner. Total tissue area, trabecular bone area, trabecular bone perimeter, and osteoclast perimeter is measured on 4 ⁇ m thick Goldner's trichrome stained sections. Percent trabecular bone area, trabecular number, trabecular thickness, trabecular separation and osteoclast perimeter as a percentage of bone surfaces are then calculated according to standardized formulae.
  • Results are analyzed using analysis of variance (group) using SAS software (SAS Institute, Cory, NC). Group comparison is performed using Dunnett's procedure using "Ovx" + vehicle group as reference group. All results are expressed as mean +/- SD.

Abstract

L'invention concerne des composés de 5-pyrrolidinone 1,2-substituée ainsi que des méthodes de traitement et des compositions pharmaceutiques utilisant ou comprenant un ou plusieurs composés de l'invention. Lesdits composés sont utilisés dans une pluralité de thérapies, notamment dans le traitement ou la prévention d'un accouchement prématuré, de la dysménorrhée, de l'asthme, de l'hypertension, de l'infertilité ou des troubles de la fertilité, d'une coagulation du sang non souhaitée, de la prééclampsie ou l'éclampsie, d'un trouble éosinophile, d'un dysfonctionnement sexuel, de l'ostéoporose ou toute autre maladie ou trouble de destruction osseuse, d'un dysfonctionnement rénal, d'un trouble d'immunodéficience, de la sécheresse oculaire, de l'ichthyose, d'une pression intra-oculaire élevée, des troubles du sommeil, de l'ulcère gastrique, ou des troubles inflammatoires et tout autre trouble ou maladie associés à la famille des composés de la prostaglandine.
EP03736967A 2002-06-10 2003-06-09 Gamma lactames utilises en tant qu'agonistes de la prostaglandine et leur utilisation Withdrawn EP1556347A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US38734002P 2002-06-10 2002-06-10
US387340P 2002-06-10
US45180403P 2003-03-03 2003-03-03
US451804P 2003-03-03
PCT/US2003/018202 WO2003103604A2 (fr) 2002-06-01 2003-06-09 Gamma lactames utilises en tant qu'agonistes de la prostaglandine et leur utilisation

Publications (2)

Publication Number Publication Date
EP1556347A2 true EP1556347A2 (fr) 2005-07-27
EP1556347A4 EP1556347A4 (fr) 2006-08-09

Family

ID=29739940

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03736967A Withdrawn EP1556347A4 (fr) 2002-06-10 2003-06-09 Gamma lactames utilises en tant qu'agonistes de la prostaglandine et leur utilisation

Country Status (6)

Country Link
US (1) US7419999B2 (fr)
EP (1) EP1556347A4 (fr)
JP (2) JP4754820B2 (fr)
AU (1) AU2003237520B2 (fr)
CA (1) CA2483555A1 (fr)
WO (1) WO2003103604A2 (fr)

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006505572A (ja) * 2002-10-25 2006-02-16 メルク フロスト カナダ アンド カンパニー Ｅｐ４受容体アゴニストとしての２−ピロリドン
WO2004065365A1 (fr) * 2003-01-21 2004-08-05 Ono Pharmaceutical Co., Ltd. Derives de 8-azaprostalangine et utilisations de ces derives en tant que medicaments
WO2006052893A2 (fr) 2004-11-08 2006-05-18 Allergan, Inc. Composes de pyrrolidone substitue therapeutique
KR101276449B1 (ko) * 2005-03-10 2013-06-20 알러간, 인코포레이티드 치료제로서의 치환된 감마 락탐
AU2012211448B2 (en) * 2005-03-10 2016-01-07 Allergan, Inc. Substituted gamma lactams as therapeutic agents
US7893107B2 (en) 2005-11-30 2011-02-22 Allergan, Inc. Therapeutic methods using prostaglandin EP4 agonist components
UY30121A1 (es) 2006-02-03 2007-08-31 Glaxo Group Ltd Nuevos compuestos
US7592364B2 (en) 2006-02-28 2009-09-22 Allergan, Inc. Substituted gamma lactams as therapeutic agents
AU2007226957B2 (en) 2006-03-20 2013-08-15 Allergan, Inc. Substituted gamma lactams as prostaglandin EP2 agonists
CA2660396A1 (fr) 2006-08-09 2008-02-21 Allergan, Inc. Amides therapeutiques et composes associes
EA015931B1 (ru) 2006-12-15 2011-12-30 Глэксо Груп Лимитед Бензамидные производные как агонисты ер-рецепторов
NZ578698A (en) * 2007-01-31 2012-04-27 Allergan Inc Substituted gamma lactams as therapeutic agents
NZ598945A (en) * 2007-02-15 2013-08-30 Allergan Inc Gamma-lactams for the treatment of glaucoma or elevated intraocular pressure
AU2008246579A1 (en) * 2007-05-08 2008-11-13 National University Corporation, Hamamatsu University School Of Medicine Cytotoxic T cell activator comprising EP4 agonist
GB0721611D0 (en) 2007-11-02 2007-12-12 Glaxo Group Ltd Novel compounds
US7960379B2 (en) 2008-03-14 2011-06-14 Allergan, Inc. Therapeutic compounds
DK2291368T3 (da) 2008-04-24 2013-03-18 Allergan Inc Substitueret gamma-lactam som terapeutisk middel
EP2149552A1 (fr) 2008-07-30 2010-02-03 Bayer Schering Pharma AG Dérivés de benzamide 5,6 substitués en tant que modulateurs du récepteur EP2
EP2149554A1 (fr) 2008-07-30 2010-02-03 Bayer Schering Pharma Aktiengesellschaft Indolylamides en tant que modulateurs du récepteur EP2
EP2149551A1 (fr) 2008-07-30 2010-02-03 Bayer Schering Pharma AG Dérivés de N-(indol-3-ylalkyl)-(hétéro)arylamide en tant que modulateurs du récepteur EP2
US7985765B2 (en) 2008-08-20 2011-07-26 Allergan, Inc. Therapeutic substituted pyrroles
WO2013090591A1 (fr) * 2011-12-15 2013-06-20 Dow Global Technologies Llc Procédé de préparation d'acides alkylpyroglutamiques
CA2879506C (fr) 2012-07-19 2020-10-27 Cayman Chemical Company, Inc. Compositions de difluorolactame destinees a des maladies et des affections osseuses mediees par ep4
CA2903314C (fr) 2013-03-15 2023-02-14 Cayman Chemical Company, Inc. Procedes de synthese d'un analogue difluorolactam
US9676712B2 (en) 2013-03-15 2017-06-13 Cayman Chemical Company, Inc. Lactam compounds as EP4 receptor-selective agonists for use in the treatment of EP4-mediated diseases and conditions
EA201591793A1 (ru) * 2013-03-15 2016-01-29 Кайман Кемикал Компани, Инк. Лактамные соединения в качестве селективных агонистов ep4-рецепторов для применения при лечении опосредованных ep4 заболеваний и состояний
EP3021879A2 (fr) 2013-07-19 2016-05-25 Cayman Chemical Company, Incorporated Procédés, systèmes et compositions pour activer la croissance osseuse

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4061643A (en) * 1975-06-18 1977-12-06 Merck & Co., Inc. Certain 16-aryloxy-11,12-seco-prostaglandins
GB1583163A (en) * 1976-05-04 1981-01-21 Hoechst Ag Pyrrolidones and process for their manufacutre
US4299970A (en) * 1974-11-29 1981-11-10 Beecham Group Limited Oxy-alkylamino carboxylic esters
EP1110949A1 (fr) * 1999-12-22 2001-06-27 Pfizer Products Inc. Agonistes sélectifs du recepteur EP4 utilisables dans le traitement de l'ostéoporose
US20020065308A1 (en) * 2000-11-27 2002-05-30 Cameron Kimberly O. EP4 receptor selective agonists in the treatment of osteoporosis
WO2003008377A1 (fr) * 2001-07-16 2003-01-30 F. Hoffmann-La Roche Ag Analogues de la prostaglandine utilises comme agonistes du recepteur ep4
WO2003009872A1 (fr) * 2001-07-23 2003-02-06 Ono Pharmaceutical Co., Ltd. Medicaments contenant un agoniste de ep4 en tant que principe actif destines aux maladies associees a une perte de la masse osseuse

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3873566A (en) * 1973-02-28 1975-03-25 Du Pont 3-Pyrazolidinones and pyrazolidines
US4033989A (en) * 1975-09-17 1977-07-05 The Upjohn Company 9-Deoxy-PGF2 Analogs
US4003911A (en) * 1975-09-26 1977-01-18 E. I. Du Pont De Nemours And Company Selected 3-pyrrolidinones and 2,4-pyrrolidindiones
JPS52102274A (en) * 1976-02-24 1977-08-27 Tanabe Seiyaku Co Ltd 8-azaprostanic acid derivatives
US4090019A (en) * 1976-05-10 1978-05-16 Minnesota Mining And Manufacturing Company Geminal prostaglandin analogs
US4211876A (en) * 1979-06-13 1980-07-08 E. I. Du Pont De Nemours And Company 3-Pyrazolidinone carboxamides
US5605814A (en) * 1993-08-31 1997-02-25 Merck Frosst Canada Inc. DNA encoding human prostaglandin receptor EP2
GB9514160D0 (en) 1994-07-25 1995-09-13 Zeneca Ltd Aromatic compounds
GB9417532D0 (en) 1994-08-31 1994-10-19 Zeneca Ltd Aromatic compounds
TW502026B (en) 1995-06-20 2002-09-11 Zeneca Ltd Aromatic compounds useful as antagonists of e-type prostaglandins, processes for the preparation thereof, pharmaceutical compositions comprising the compounds, and intermediates
TW434240B (en) 1995-06-20 2001-05-16 Zeneca Ltd Aromatic compounds, preparation thereof and pharmaceutical composition comprising same
EP0752421B1 (fr) 1995-07-07 2005-10-12 AstraZeneca AB Composés aromatiques substitués en position ortho, contenant trois groupes (het)aryle, leur préparation et leur utilisation comme antagonistes de prostaglandine E2-(PGE2)
UA59384C2 (uk) * 1996-12-20 2003-09-15 Пфайзер, Інк. Похідні сульфонамідів та амідів як агоністи простагландину, фармацевтична композиція та способи лікування на їх основі
WO2000015608A1 (fr) * 1998-09-14 2000-03-23 Ono Pharmaceutical Co., Ltd. Derives e de phenyl-prostaglandine a substitution-φ et medicaments les contenant comme ingredient actif
US6211197B1 (en) * 1998-10-07 2001-04-03 Merck Frosst Canada & Co. Prostaglandin receptor ligands
DK1132086T3 (da) * 2000-01-31 2006-08-28 Pfizer Prod Inc Anvendelse af prostaglandin (PGE2) selektive receptor 4 (EP4) agonister til behandling af akut og kronisk nyresvigt
WO2001066518A1 (fr) * 2000-03-09 2001-09-13 Ono Pharmaceutical Co., Ltd. E-ALCOOLS PHENYL-PROSTAGLANDINE φ-SUBSTITUES, PROCEDE DE PREPARATION ASSOCIE ET MEDICAMENTS RENFERMANT CES DERNIERS EN TANT QUE PRINCIPE ACTIF
WO2002024647A1 (fr) 2000-09-21 2002-03-28 Ono Pharmaceutical Co., Ltd. Agonistes du recepteur de l'ep4 comprenant comme principe actif des derives de la 8-azaprostaglandine
BR0211167A (pt) 2001-07-16 2004-08-10 Hoffmann La Roche Derivados de 2-pirrolidona como agonistas de prostanóides
JP4547912B2 (ja) * 2002-03-05 2010-09-22 小野薬品工業株式会社 ８−アザプロスタグランジン誘導体化合物およびその化合物を有効成分として含有する薬剤

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4299970A (en) * 1974-11-29 1981-11-10 Beecham Group Limited Oxy-alkylamino carboxylic esters
US4061643A (en) * 1975-06-18 1977-12-06 Merck & Co., Inc. Certain 16-aryloxy-11,12-seco-prostaglandins
GB1583163A (en) * 1976-05-04 1981-01-21 Hoechst Ag Pyrrolidones and process for their manufacutre
EP1110949A1 (fr) * 1999-12-22 2001-06-27 Pfizer Products Inc. Agonistes sélectifs du recepteur EP4 utilisables dans le traitement de l'ostéoporose
US20020065308A1 (en) * 2000-11-27 2002-05-30 Cameron Kimberly O. EP4 receptor selective agonists in the treatment of osteoporosis
WO2003008377A1 (fr) * 2001-07-16 2003-01-30 F. Hoffmann-La Roche Ag Analogues de la prostaglandine utilises comme agonistes du recepteur ep4
WO2003009872A1 (fr) * 2001-07-23 2003-02-06 Ono Pharmaceutical Co., Ltd. Medicaments contenant un agoniste de ep4 en tant que principe actif destines aux maladies associees a une perte de la masse osseuse

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO03103604A2 *

Also Published As

Publication number Publication date
WO2003103604A3 (fr) 2004-02-12
AU2003237520B2 (en) 2009-01-08
AU2003237520A1 (en) 2003-12-22
JP2005533043A (ja) 2005-11-04
EP1556347A4 (fr) 2006-08-09
JP4754820B2 (ja) 2011-08-24
CA2483555A1 (fr) 2003-12-18
US20050288357A1 (en) 2005-12-29
US7419999B2 (en) 2008-09-02
JP2011063622A (ja) 2011-03-31
WO2003103604A2 (fr) 2003-12-18

Similar Documents

Publication Publication Date Title
US7419999B2 (en) Gamma lactams as prostaglandin agonists and use thereof
JP4550417B2 (ja) プロスタグランジンｅｐ２及び／又はｅｐ４受容体のリガンドとしてのポリアゾリジノン化合物
US8058305B2 (en) Pyrrolidine derivatives as prostaglandin modulators
AU2002340282A1 (en) Pyrazolidinone compounds as ligands of the prostaglandin EP2 and/or EP4 receptors
US7276531B2 (en) G-lactam derivatives as prostaglandin agonists
EP1824819B1 (fr) Derives de pyrrolidin-2-one utiles comme agonistes du recepteur dp1
WO2004012656A2 (fr) Derives de thiophene et de furanne en tant qu'agonistes de la prostaglandine et utilisation associee
US7465755B2 (en) Hydrazide derivatives as prostaglandin receptors modulators
DE2346706A1 (de) Neue, nicht natuerlich vorkommende analoga von prostansaeuren und verfahren zu ihrer herstellung

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20050105

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

A4 Supplementary search report drawn up and despatched

Effective date: 20060712

17Q First examination report despatched

Effective date: 20061108

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: LABORATOIRES SERONO SA

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: MERCK SERONO SA

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20121002